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Review

Paying Homage to Microvessel Remodeling and Small Vessel Disease in Neurodegeneration: Implications for the Development of Late-Onset Alzheimer’s Disease

Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65211, USA
J. Vasc. Dis. 2024, 3(4), 419-452; https://doi.org/10.3390/jvd3040033
Submission received: 1 November 2024 / Revised: 15 November 2024 / Accepted: 18 November 2024 / Published: 20 November 2024
(This article belongs to the Section Neurovascular Diseases)

Abstract

:
The microvessel neurovascular unit, with its brain endothelial cells (BEC) and blood–brain barrier remodeling, is important in the development of impaired cognition in sporadic or late-onset Alzheimer’s disease (LOAD), which is associated with aging and is highly prevalent in older populations (≥65 years of age). It is also linked with vascular dementia and vascular contributions to cognitive impairment and dementia, including cerebral amyloid angiopathy in neurodegeneration. LOAD is considered to be the number one cause of dementia globally; however, when one considers the role of mixed dementia (MD)—the combination of both the amyloid cascade hypothesis and the vascular hypothesis of LOAD—it becomes apparent that MD is the number one cause. Microvessel BECs are the first cells in the brain to be exposed to peripheral neurotoxins from the systemic circulation and are therefore the brain cells at the highest risk for early and chronic injury. Therefore, these cells are the first to undergo injury, followed by excessive and recurrent wound healing and remodeling processes in aging and other age-related diseases such as cerebrocardiovascular disease, hypertension, type 2 diabetes mellitus, and Parkinson’s disease. This narrative review explores the intricate relationship between microvessel remodeling, cerebral small vessel disease (SVD), and neurodegeneration in LOAD. It also discusses the current understanding of how microvessel dysfunction, disruption, and pathology contribute to the pathogenesis of LOAD and highlights potential avenues for therapeutic intervention.

Graphical Abstract

1. Introduction

The role of macrovascular and microvascular remodeling in the development of neurodegeneration and dementia in sporadic or aging-related late-onset Alzheimer’s disease (LOAD), as compared to genetic-related early-onset Alzheimer’s disease (EOAD), has undergone numerous historic pendulum swings since the early 1900s [1,2,3,4]. Numerous descriptive hypotheses regarding the causes of LOAD have been considered over the years, including the aging-related hypothesis, cholinergic hypothesis, amyloid cascade hypothesis, tau propagation hypothesis, mitochondrial cascade hypothesis, calcium homeostasis hypothesis, inflammatory hypothesis, metal ion hypothesis, genetic/environmental hypothesis, and the vascular/neurovascular hypothesis (Box 1) [5,6,7].
Box 1. Major existing hypotheses and evolving concepts for late-onset Alzheimer’s disease (LOAD). While this box individually lists the ten major hypotheses and two emerging concepts for the development of LOAD, it is important to note that these major hypotheses interact and that the development of LOAD is thought to be caused by a complex interaction or combination of these hypotheses. Note the red double arrows that indicate a vicious cycle between hypotheses V (Neuroinflammation) and VI (Oxidative Redox Stress). AD, Modified box image is provided with permission by CC 4.0 [6]. Alzheimer’s disease; aMt, aberrant mitochondria; aMGCs, aberrant microglia cells; aMt, aberrant mitochondria; APOE-ε4, apolipoprotein E epsilon 4; BOLD, blood oxygen level-dependent imaging; CBF, cerebral blood flow; LOAD, late-onset Alzheimer’s disease; MGC, microglia cell; Mt, mitochondria; OxRS, oxidative redox stress; PET, positron emission tomography; ROS, reactive oxygen species; T1DM, type 1 diabetes mellitus.
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The initial aging and vascular hypothesis held strong for many decades; however, once the amyloid cascade hypothesis was suggested in 1991, the pendulum quickly swung to this hypothesis as the most likely leading cause for LOAD [8,9]. Additionally, Swerdlow and Khan importantly proposed a mitochondrial cascade hypothesis, with redox stress as a leading cause for sporadic Alzheimer’s disease or LOAD, in 2004 [10]. Notably, the amyloid cascade hypothesis may be somewhat flawed; while amyloid beta (Aβ) by itself may be necessary for the development of LOAD, it is not sufficient to be the primary cause [11].
The old adage that “what goes around comes around” has taken hold. This current terminology regarding the vascular/neurovascular microvessel remodeling hypothesis is quite prevalent in the literature and is used to refer to vascular contributions to cognitive impairment and dementia (VCID), as depicted in Box 1, IX [5,6]. VCID encompasses all types of cerebrovascular and cardiovascular disease-related conditions associated with impaired cognition and cognitive decline.
Microvessel cerebral small vessel disease (SVD) is considered to be the most important vascular contributor to cognitive decline and dementia [12]. Importantly, Jacob et al. were able to share that SVD baseline severity and progression were independently associated with an increased risk of all-cause dementia over a follow-up of 14 years, with progression of white matter hyperintensities (WMH) predicting incident all-cause dementia [12].
Due to its proven ability to prevent and treat cardiovascular diseases, including hypertension, the NIH has recently designated VCID as a critical focus of research [13]. Moreover, the recent MarkVCID Biomarker Development and Validation Consortium has been designed to better predict, study, and diagnose SVD in the brain and its role in VCID. The National Institutes of Health (NIH) has launched MarkVCID, to accelerate the development of new and existing biomarkers for small vessel VCID. The overall goal of the consortium is to deliver high-quality biomarkers that are ready for use in clinical trials aimed at generating scientific breakthroughs in our understanding and treatment of VCID [13].
Brain microvessels may be defined as penetrating arterioles, precapillary arterioles, capillaries, postcapillary venules, and ascending venules measuring ≤500 μm, which may have only one or two layers of VSMC in their media or just a single layer of pericytes (Pcs) (Figure 1) [1,2].
Thus, microvessels are structurally designed to function both as resistance and transport microvessels, which allow for the regulation of hydrodynamics and the exchange of nutrients and waste products, oxygen and carbon dioxide, and water within the central nervous system (CNS) [1,2,3,4,5,6,7,8,9,10,11,12,13,14].
Microvessel SVD refers to a variety of structural and functional changes involving small perforating arterioles, capillaries, and ascending venules in the brain [14]. Furthermore, these SVDs are broken down into at least four main categories—lacunes, enlarged perivascular spaces (EPVS), WMH, and cerebral microbleeds (CMBs)—as identified by magnetic resonance imaging (MRI) (Box 2) [1,14].
Box 2. Comparing the four major identifiable structures of cerebral small vessel disease (SVD) by MRI observations: (1) lacunes (a footprint of stroke); (2) enlarged perivascular spaces (EPVS) (a biomarker of glymphatic system pathway dysfunction (GLY Dys)); (3) white matter hyperintensities (WMH) (footprint of ischemia); (4) cerebral microbleeds (CMBs) (biomarkers of SVD/stroke with hemorrhage or ischemic infarct); and (5) recent small subcortical infarcts (MRI representative findings of recent infarction similar to lacune parameters but with greater flair, suggesting recent occurrence, not presented in this figure). The location of CMBs has further clinical importance in that lobar/cortical CMBs are CAA-related and deep, basal, infratentorial CMBs are hypertension-related. Modified figure image provided with permission by CC 4.0 [1]. Asterisk, denotes emphasis; CAA, cerebral amyloid angiopathy; mm, millimeter; MRI, magnetic resonance imaging.
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SVD is a group of microvessel diseases that affect small arteries, precapillary arterioles, and postcapillary venules in the brain, and can manifest as lacunes, EPVS, WMH, and CMBs capable of promoting the development of neurodegeneration [14,15].
It is important to note here that when utilizing TEM microscopy, one cannot visually observe how the protoplasmic perivascular astrocytes endfeet (pvACef) connect with regional neurons to create neurovascular unit (NVU) coupling. The NVU (Figure 2) consists of the BECs that line the vascular lumen—the pericytes that are formed within the basement membrane (BM)—which supports the BECs and contributes to the synthesis and maintenance of the tight and adherens junctions (TJ/AJ), junctional adhesion molecules (JAMs), and vascular endothelial cadherin(s) (VE-Cads or cluster of differentiation CD144) responsible for creating the blood–brain barrier (BBB). It also shows the adjacent protoplasmic perivascular astrocyte endfeet (pvACef) that adhere tightly to the combined BEC and pericyte BM, which communicate via astrocyte cytoplasmic processes to regional neurons, neuronal dendritic synapses, and terminal axon synapses that form a tripartite synapse (Figure 2) [16,17,18,19,20].
Notably, pvACs with their endfeet are the master connecting cells of the CNS [3,16,21].
While this narrative review focuses on microvessel SVD remodeling, it is important to briefly discuss the role of macrovessel remodeling in both the extracranial and intracranial macrovessels (≥5 μm with more than two layers of vascular smooth muscle cell(s) (VSMCs) within their media). Macrovessels are capable of undergoing primarily atherosclerotic and arteriolosclerotic remodeling that result in the development of stroke-prone regions of involvement. This macrovessel remodeling results in decreased cerebral blood flow (CBF) and ischemic strokes, not only due to decreased CBF but also thromboembolic phenomena. These mechanisms make macrovessel remodeling a significant factor in ischemic stroke, which is the number one cause of stroke and impaired remodeling. The decreased CBF and/or ischemic stroke result in increased redox stress, neuroinflammation, neurodegeneration and vascular cognitive impairment or dementia (VaD) or VCID [22,23,24].
Just as LOAD is a multifactorial and heterogenous aging-related neurological disease [23,25], neurodegeneration (ND) is also a complicated multifactorial process, due to the slow development of CNS neuronal atrophy and loss resulting from programmed cell death–an important final step in the development of dementia [26]. In this narrative, we will focus on ND caused by misfolded proteins, including the accumulation of toxic oligomers of extracellular Aβ. These include CNS Aβ (1–42), which forms interstitial senile or Aβ plaques (LOAD), and primarily Aβ (1–40), which accumulates within precapillary arterioles in the interstitial and perivascular adventitia basement membranes and extracellular matrix (ECM) associated with cerebral amyloid angiopathy (CAA). While not the focus of this narrative, it is important to note that intracellular misfolded tau proteins form misfolded neurofibrillary tangles (NFTs) due to aberrant hyperphosphorylation, which promotes neuronal dysfunction, impaired cognition, and neurodegeneration [5].
Notably, Iturria-Medina et al. (2016) have stated that vascular dysregulation and microvessel remodeling might be the earliest and strongest brain pathologic factor associated with LOAD development, which is followed by Aβ deposition, misfolded tau formation with neurofibrillary tangles, glucose metabolism dysregulation, functional impairment, neuronal apoptosis, and grey matter atrophy [3].
Dementia is an umbrella term which encompasses four types of dementia including (i) Alzheimer’s—LOAD dementia, (ii) VaD, co-occurring or mixed dementias (MD), (iii) frontal temporal dementia, and (iv) Lewy body dementia [23]. Herein, the discussion will primarily focus on SVD, VaD/VCID, and Alzheimers disease or LOAD. Indeed, sporadic and age-related neurodegenerative disorders such as LOAD are the consequence of aging-associated multifactorial biological dysfunction with a heterogenous background [3,4,27].
When studying chronic age-related diseases such as co-occurring VaD with LOAD, which includes both arterial macrovessel disease and microvessel SVD, it is important to understand structural remodeling [27]. Microvessel remodeling, as a result of chronic peripherally derived neurotoxic metabolic alterations, as it relates to concurrent remodeling of arterioles, precapillary arterioles, the true capillary, the postcapillary venules and veins in development of vascular remodeling and SVD and neurodegeneration, is very complicated. Thus, it seems appropriate to pay homage to the cerebral microvessels and their component cells, consisting of BECs, Pcs, and connecting astrocyte endfeet, which result in the formation of the NVU of the brain to control CBF, which in turn provide nourishment and oxygen delivery to neuronal cells for proper function via the NVU coupling mechanisms.
The widely accepted current hypothesis of neurodegeneration in LOAD has previously been widely centered around abnormal misfolded amyloid and tau protein aggregation. This hypothesis has recently undergone some changes and more researchers are now pointing to the importance of the macro- and microvascular contributions to neurodegeneration [14,15,22,23,24,27,28,29,30,31,32]. Emerging evidence suggests that endothelial dysfunction is an early and primary event in AD pathogenesis that may precede abnormal protein aggregation and directly contribute to neurodegeneration and synaptic injury [31]. Importantly, microvessel SVD has been increasingly recognized as a significant contributor to the development of neurodegeneration via the following phenomena: (1) microvessel SVD dysfunction and damage [14]; (2) WMH changes and neurodegeneration [30,33]; (3) capillary NVU blood–brain barrier dysfunction [34]; (4) inflammation and neurodegeneration [23]; and (5) cerebral microbleeds and neurodegeneration [35,36].
Multiple transmission electron microscopic images are utilized throughout this narrative review, which were primarily derived from obese, insulin-resistant, type 2 diabetes mellitus mice female db/db models and their controls, unless otherwise specified. While this review is focused on human individuals with LOAD, these obese, diabetic mouse models’ brain tissues were derived from frontal cortical layer III, unless otherwise specified. They are only intended to serve as examples of the brain microvascular normal and remodeling ultrastructure changes.
The primary focus of this narrative is the microvessel and SVD of the neurovascular hypothesis and their effects on the development of LOAD. However, it is important to note the overwhelming evidence that LOAD is a multifactorial progressive disease with multiple targets and hypotheses capable of interacting (Box 1) that will require a multi-targeted treatment approach.
The primary goal of this narrative review is to enhance our knowledge of the important role of the microvessel and SVD in the development and progression of LOAD, since this may result in a clarifying contribution to this field of study.

2. Vascular-Neurovascular Hypothesis: Microvessel Remodeling and Cerebral Small Vessel Disease (SVD) Contributions to Neurodegeneration

Human clinical, experimental, epidemiological, and preclinical animal studies have provided increasing evidence that aging-associated cerebromicrovascular dysfunction and microvessel damage play critical roles in the pathogenesis and pathobiology of LOAD and VaD that may also be involved in other dementias. Indeed, we currently stand on the shoulder of giants in this field, as reflected in many prior references and future references in this section.
Cerebral microvessel remodeling may be simply defined as a structural rearrangement and an adaptive and/or maladaptive process that occurs in a long-term, chronic response to changes in hemodynamic conditions or the effects of injurious neurotoxic stimuli, as in the wound-healing mechanism [37].

2.1. Neurovascular Unit Brain Endothelial Cells and Brain Endothelial Cell Activation and Dysfunction (BECact/dys)

BECs are the first cells to be exposed to multiple injurious species (neurotoxins) from the peripheral systemic circulation and are the first cells in the brain to undergo functional and structural remodeling (Figure 3) [36,37,38,39].
Brain insulin resistance, and specifically BEC insulin resistance, plays an important role in the development of BECact/dys and blood–brain barrier dysfunction and disruption (BBBdd). This process involves decreased bioavailable nitric oxide, increased vascular inflammation, and increased BBB permeability. Furthermore, the interaction of advanced glycation end-products with their receptor (RAGE) leads to increased OxRS and neurodegeneration associated with LOAD [6,39,40]
Over the past decade, the author has been able to discern at least ten major transmission electron microscopic (TEM) ultrastructural remodeling changes in microvessel BECact/dys phenotypes (Box 3) [1,40].
Box 3. Ten major transmission electron micrograph (TEM) aberrant remodeling changes associated with brain endothelial cell activation and dysfunction (BECact/dys) to better understand the various brain endothelial cell responses to wound-healing phenotypes. Image reproduced with permission by CC 4.0 [1,40].
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BECact/dys and BBBdd with increased permeability either simultaneously co-occur or occur immediately following BECact/dys (Figure 4) [2,39,40,41].
In addition to leukocyte (vascular neuroinflammation) and erythrocyte adhesion to the activated BEC, as shown in Figure 4 there is also an attenuation and/or loss resulting from discontinuation and interruption of the endothelial cell glycocalyx (ecGCx) due to an increase in BEC pinocytosis/transcytosis (Figure 5) [40,41,42].
BEC tight and adherens junctions (TJ/AJ) undergo attenuation and or loss with discontinuation. This leaves open gaps that allow for increased permeability of peripheral neurotoxins into the neuropil in LOAD. An example of TJ/AJ aberrant remodeling attenuation and/or loss is provided by the streptozotocin-induced type 1 diabetes model (Figure 6) [43].

2.2. Neurovascular Unit Pericyte (Pc) Remodeling

Brain NVU Pcs are known to interact with BECs, basal lamina (basement membrane), and glial cells. They play a critical supportive role in the synthesis and maintenance of BBB-TJ/AJ, providing stability and local control of regional capillary blood flow through NVU coupling via Acs. They also contribute to angiogenesis and immune responses, as they are recognized as antigen-presenting cells [44,45,46,47]. Brain NVU Pcs are mural vascular support cells of the BBB, partially responsible for the synthesis and maintenance of the BBB TJ/AJ structures. These structures undergo degeneration in LOAD, a neurodegenerative disease that is characterized by early neurovascular dysfunction and uncoupling. This degeneration is associated with the elevation of amyloid β-peptide (Aβ), tau pathology, and neuronal apoptosis and loss. These changes lead to progressive cognitive impairment, neurodegeneration, and dementia [46]. BEC and Pc interactions and connections are crucial for proper NVU function and maintain CBF to regional active neurons, leading to NVU coupling along with the necessary function of NVU pvACef (Box 4) [44,45,46,47,48,49,50,51,52,53,54,55].
Brain Pcs are known to integrate, coordinate, and process signals from their neighboring cells in the NVU to generate diverse functional responses that are critical for CNS homeostatic functions in health and pathologic remodeling and dysfunction in disease. These responses in health include regulation of the blood–brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses (vasodilation and contraction), and neuroinflammation. Pcs and BECs both are capable of acting as antigen-presenting cells (APCs), while Pcs also have the potential to become mesenchymal stem cells due to their pleiotropic potential [44,45,46,47,48,49,50,51,52,53,54,55,56]. Furthermore, brain NVU pericytes not only provide structural support to the NVU BECs, but are also perfectly positioned within the NVU to facilitate peripheral systemic metainflammation that may result in BECact/dys and BBBdd (Figure 7) [44].
Box 4. Pericyte and brain endothelial cell protein interactions and interdependent biomarkers and signaling proteins. Image modified with permission by CC 4.0 [44,45]. a -SMA, alpha-smooth muscle actin; eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; LDL-C R, low-density lipoprotein-C receptor; NG2, neuroglia 2; PDGF-B, platelet-derived growth factor-B; PDGF-B (R), receptor for PDGF-B; VEGF A (Pc positive (+), B (BEC +)), vascular endothelial growth factor A, B; Shadowing, denotes emphasis; vWf, von Willebrand factor.
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Notably, vascular endothelial growth factor A (VEGFA) is secreted by Pcs and signals BEC VEGFR1 or Flt-1 to result in BEC migration, proliferation, and remodeling of its structure, resulting in angiogenesis [57]. In contrast, VEGFB is secreted by BECs and has a potent survival/anti-apoptotic effect, while lacking a general angiogenic activity [58].
NVU Pcs are known to be very sensitive to oxidative-redox stress in addition to pCC due to leaky BECact/dys and BBBdd [46,50,51,58]. Pc sensitivity to redox stress and neuroinflammation contributes to aberrant structural remodeling, dysfunction, degenerative remodeling changes and loss due to apoptosis, formation of ghost cells, NVU dysfunction with NVU uncoupling, decreased regional CBF with ensuing hypometabolism, hypoxia, and neurodegeneration (Figure 8) [6,41,59,60,61].
Additionally, Aβ (1–42) extracellular-interstitial plaques and toxic oligomers result in BECact/dys with increased BEC-derived ROS (primarily from membranous NADPH oxidases (Nox1)) and mitochondrial ROS. This leads to Pc activation, dysfunction, and/or degeneration due to redox stress caused by the BECact/dys, with increased local paracrine signaling to adjacent Pcs via the powerful BEC-derived vasoconstrictor endothelin 1 (ET-1) as a result of redox stress and ROS (Figure 9) [62].
Furthermore, BEC-derived ET-1 signaling results in Pc vasoconstriction and ensuing decreased regional NVU CBF with hypometabolism, hypoperfusion, and ischemia/hypoxia associated with degenerative neurites, as observed in Figure 9. These are indicative of neurodegeneration and impaired cognition [62].
Pcs independently and Pc-BEC interactions play critical roles in maintaining normal NVU coupling [63]. Pcs are mural cells in the brain, and this provides a unique location for BEC/Pc interactions with paracrine signaling in cerebral small vessels of the NVU and also allows Pcs to occupy nearly 80% of the abluminal side of BECs [64]. Pcs also act as an intermediary cell sandwiched between the luminal BECs and abluminal pvACef within a shared BM by regulating endothelial activity such as TJ/AJ formation and transcytosis, in addition to guiding pvACef polarization and attachment to the outer BM [50,65].

2.3. Brief Overview of Neurovascular Unit (NVU) Reactive Perivascular Astrocyte(s) (rpvACs) and Reactive Microglia Cells (rMGCs) That Contribute to Neurodegeneration (ND)

Glial astrocyte(s) (ACs) are considered to be one of the most abundant cells within the CNS. Through their innate connection and communication functions, they play an important and essential role in maintaining homeostasis and structural support, as previously depicted in Figure 2 and Figure 10 [16].
ACs are also known to be master communicating/connecting cells in the brain that connect the NVU to regional neurons and synapses. In doing so, they provide homeostatic coupling, provision for synapse formation, maintenance, and support via their cradling effect, in addition to their pruning effects along with MGCs, as in previous Figure 2 (Figure 11) [16,17,18,19,20,21].
Additionally, ACs are a major supplier of energy to regional neurons in the form of glucose and lactate, as they are able to store glycogen and can undergo glycolysis. Additionally, ACs are a major source of antioxidant reserve via glutathione and superoxide dismutase. They also have the capability to provide necessary growth factors such as brain-derived growth factor (BDGF), transforming growth factor-beta (TGF-β), nerve growth factor (NGF), insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), transforming growth factors alpha (TGF)-α and TGF-β, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF). All of these factors have been shown to exert neuroprotection [66,67,68,69].
While this narrative is focused primarily on NVU BEC microvessel remodeling and their contribution to SVD, the reactive pvACef (rpvACef) and rMGCs remodeling are also known to be associated with NVU uncoupling (Figure 12) [60].
In addition to the rpvACs and rMGCs shown in Figure 12, there is another proinflammatory cell that is now known to reside within the perivascular spaces of the perivascular unit when BECact/dys and BBBdd occur. This cell is the reactive perivascular macrophage (rPVMΦ), which has been identified within the perivascular spaces of microvessels in neuroinflammatory-induced lipopolysaccharide (LPS)-treated models (Figure 13) [45,59,70,71].
NVU uncoupling is associated with decreased CBF with hypoperfusion, hypometabolism, hypoxia, and ischemia to regional neurons, resulting in impaired cognition and neurodegeneration. Further, aberrant cerebrovascular reactivity is associated with NVU uncoupling, which is a common and prominent feature in the human brain during the early stages of the aging mild cognitive impairment (MCI)-LOAD spectrum [72].
rACs are capable of multipotential remodeling phenotypes in LOAD. Individuals with LOAD are exposed to multiple injurious stimuli such as ischemic and or hemorrhagic stroke, which result in rACs, rMGCs, central nervous system cytokines/chemokines (cnsCC), ROS, and activation of matrix metalloproteinases 2, 9 (MMP 2, 9) [28]. Importantly, following these injuries, a protective astrogliosis scar is formed to protect the brain [28]. Additionally, it is known that Aβ oligomers and Aβ extracellular plaques are neurotoxic and are capable of inducing an atrophic rAC phenotype that is capable of causing synaptic connection disruptions, imbalance of neurotransmitter homeostasis, and even neuronal death via increased excitotoxicity [73]. Neurotoxic Aβ oligomers and plaques induce primarily rACs with an atrophic phenotype, in contrast to the palisading and hypertrophic rACs in glia scar formation (Figure 14) [73,74,75].
Importantly, soluble Aβ oligomers are more important in the induction of neurotoxicity than the histopathologic mature footprint of extracellular Aβ plaques [76]. Indeed, Zlokovic has illustrated in a schematic the involvement of NVU BBB loss of integrity with impaired clearance of Aβ soluble oligomers, which results in their accumulation and an increase in the early phase of neurodegeneration in LOAD development associated with the importance of the neurotoxic effects of soluble Aβ accumulation [77]. Thus, this schematic emphasizes the neurotoxicity of both reduced CBF and the accumulated soluble Aβ oligomers, as they negatively affect synaptic impairment and promote neuronal loss due to apoptosis with neurodegeneration and impaired cognition.

3. Neural Oxidative Redox Stress (OxRS) Including: ROS, Reactive Oxygen, Nitrogen, Sulfur Species (RONSS), and Iron Sulfur Clusters (ISCs) of the Reactive Species Interactome (RSI)

LOAD and/or MD may be defined by the accumulation of two types of insoluble misfolded, fibrous proteins, i.e., extracellular amyloid-β peptide deposited in extracellular Aβ plaques, and intracellular NFTs composed primarily of abnormal and hyperphosphorylated tau proteins. In addition to Aβ plaques and intracellular NFTs, LOAD may be further pathologically characterized by regional neuronal death and atrophy, which are associated with dysfunctional synapses or the loss of synaptic connections [1,2,3,4,78]
Redox homeostasis describes the normal physiologic process of reduction and oxidation in order to repair unstable, damaging, reduced ROS, which includes oxygen free radicals such as superoxide, (O2●−), (hydrogen peroxide (H2O2), hydroxyl radical (OH), singlet oxygen (1O2), and reactive nitric oxide (NO), along with organic analogues which include reactive nitrogen species (RNS), primarily peroxynitrite (ONOO-) [79,80,81]. Oxidative stress implies a loss of redox homeostasis (imbalance) with an excess of ROS by the singular process of oxidation. Both redox and oxidative stress may be associated with an impairment of antioxidant defensive capacity, as well as an overproduction of ROS. Oxidative redox stress (OxRS) implies a loss of this unique homeostasis, resulting in an excess production of ROS either through the process of oxidation or reduction. Also, reactive iron and sulfur clusters (ISCs) are important regarding OxRS including ROS, RONSS, and the entire reactive species interactome in the brain, and are generated by mitochondria as mitochondria ROS (mtROS) and ISCs (Figure 15) [80,82,83,84].
Notably, OxRS is known to result in dysfunctional and damaged proteins, lipids, and nucleic acids (RNA and DNA) that result in multiple biomarkers of OxRS in the brain as oxidatively modified proteins such as protein carbonyls and 3-nitrotyrosine.
Each of the component cells of the microvascular NVU (BECs, Pcs, pvACef, and MGCs) are capable of generating large amounts of ROS and proinflammatory cnsCC when they become activated as in BECact/dys, or reactive as in rPcs, rACs, or rMGCs, due to various injurious stimuli with the formation of aberrant mitochondria (aMt) as in Figure 8A–E and Figure 15 wherein aMt generate not only ROS but also redox reactive prooxidative iron and sulfur species (ISCs) and increased NOX activity [28,36]. Additionally, ROS and/or OxRS are known to form a vicious cycle with neuroinflammation and ROS instigating ROS (Figure 16) [28,36,85].

4. Neuroinflammation and Neurodegeneration

As shown in Figure 16, since OxRS/oxidative stress is involved in a vicious cycle with neuroinflammation, which contributes to neurodegeneration. This cycle can lead to sustained inflammation that can be detrimental long after the initial trigger. This inflammation contributes not only to microvessel SVD but also to neurodegeneration and impaired cognition, as observed in LOAD (Figure 17) [36].
Neuroinflammation is one of the central features of LOAD, and proinflammatory CNS cytokine/chemokine cnsCC signaling plays multiple roles in neurodegeneration. Further, neuroinflammation may be characterized by multiple cnsCCs, which not only participate with OxRS in vicious cycles and hits, as shown in Figure 16 and Figure 17, but are also capable of inducing neurodegeneration independently (Figure 18) [86,87].
Indeed, chronic CNS neuroinflammation induces neurodegeneration.

5. Neurodegeneration

LOAD and/or MD (LOAD plus VaD) are the leading causes of sporadic dementias in the aging population [23,88,89]. Individuals with LOAD/MD experience clinical symptoms of cognitive impairments, memory loss (especially recent memory loss), and behavioral changes that interfere with activities of daily living [90,91]. The dementia associated with LOAD/MD is linked to neurodegeneration, which is characterized initially by synaptic injury, dysfunction, and/or loss [92,93], followed by neuronal loss [94]. These findings are further accompanied by rACs and astrogliosis [95], rMGC proliferation [96,97], and the presence of neurofibrillary tangles composed of dystrophic neurites and hyperphosphorylated tau [92,98,99,100,101,102].
These changes include multiple defective cellular processes, such as aMt remodeling (as shown in Figure 8A–E), resulting in dysfunctional leakage of mtROS, increased OxRS from all cells of the NVU (BECs, Pcs, and reactive ACs and MGCs and neurons, lysosomal dysfunction with decreased disposal of Aβ aggregates and oligomers, and increased inflammation (cnsCC) with subsequent associated apoptotic loss and neurodegeneration as in Figure 8F and Figure 18 [89].
In regard to neurodegeneration and neuronal death, there are four major cellular death pathways including necrosis, apoptosis, excitatory, and autophagic. In MD, there would be at least two different neuronal cell death pathways namely apoptosis in LOAD and ischemic necrosis in VaD [103].
Mitochondria are an important neuronal organelle producing reactive oxygen species (ROS) in addition to plasma membranous NADPH oxidase (Nox1) in LOAD [104,105]. According to Xie et al., leaky aMt could be considered the central pawns in the development of neurodegeneration and loss via neuronal apoptosis and LOAD, as illustrated in Figure 8E,F [105]. Increased and accelerated accumulation of Aβ plaque aggregation and deposition within the CNS ECM plaques in LOAD associate with increased soluble Aβ oligomers as in Figure 8 and Figure 9A. Indeed, these findings result from an imbalance in Aβ production, aggregation, and impaired clearance [89], which is associated with the development of SVD and the identification of EPVS by MRI. Aβ clearance is mediated by proteolytic enzymes such as neprilysin [106], chaperone molecules such as ApoE in health [107], lysosomal autophagy [108], and non-lysosomal pathways via the proteasome [109] in health, which is impaired in LOAD/MD. It is currently thought that soluble Aβ oligomers, rather than the fibrils within Aβ plaques, are responsible for the neurotoxic effect on synapses and neurons associated with neurodegeneration [76,110,111].
It is important to note that SVD is capable of promoting and contributing to the development of neurodegeneration (Figure 19) [14,15].
Furthermore, Crews and Masliah have proposed the following sequences for neurogenic development with impaired cognition observed in LOAD. The neurotoxic effects of Aβ plaque and its oligomers result in signaling alterations in neuronal neurodegenerative kinases including Fyn, FAK, GSK3β, and CDK5. These alterations result in alterations to cytoskeletal and synaptic proteins, resulting in tau-derived neurofibrillary tangles (NFTs). aMt result in leaky neurotoxic mtROS, neuronal oxidative/redox stress, impaired lysosomal uptake, and proteolysis, which are associated with cnsCCs. This all proceeds to neurodegeneration, consisting of synaptic injury and dysfunction, defects in neurogenesis, and impaired cognition in LOAD, along with neuronal apoptosis and loss with cerebral atrophy [89].
Cerebral atrophy is a persistent core marker finding on MRI in LOAD and MD (VaD + LOAD) in both rodent animal models (such as the female diabetic db/db mouse model at 26-weeks of age) and aging human individuals (Figure 20) [111,112,113].
Additionally, there is significant dysfunction and/or loss of synaptic transfer of information at degenerative synapses in LOAD and MDs, which contributes to the development of neurodegeneration, impaired cognition, and dementia [116,117,118,119].

6. Cerebral Amyloid Angiopathy (CAA) Role in the Development and Progression of LOAD

CAA is associated with the development and progression of LOAD and was only briefly discussed in the legend of Box 2 earlier in Section I. However, CAA is important because it is also associated with advancing age and is considered to be part of the SVD spectrum, which is also incorporated into VCID and primarily occurs in leptomeningeal and cortical blood vessels. Deposition of Aβ occurs primarily within the VSMC media and adventitia of vessels, with a propensity to bind to basement membranes and extracellular matrix proteins of the adventitia. This results in fragile, vulnerable microvessels that are leaky and prone to rupture, resulting in hemorrhages. Notably, CAA is the second most common cause of cerebral hemorrhage in the elderly after hypertension causing cerebral hemorrhage in the elderly, accounting for 15–40% of non-traumatic cerebral hemorrhages in the elderly, with a mortality rate of 30–50%, according to Qi [120].
In particular CAA is related to CMBs, and their location is important. CAA is related to lobar cortical CMBs, while basilar and infratentorial CMBs are related to hypertension, according to WangL [121]. Indeed, CAA is associated with CMBs and cortical intracerebral hemorrhages, which are a common cause for hemorrhagic stroke. Interestingly, in CAA, the Aβ (1–40) isoform is most prevalent. This is in contrast with parenchymal/interstitial Aβ plaques, in which Aβ (1–42) is the most prevalent isoform.
Sporadic CAA is the most common type of CAA, especially in elderly populations, and is associated with LOAD. At autopsy, CAA in individuals with LOAD has a prevalence of at least 48%, and individuals with LOAD have an 80% or greater co-occurrence of CAA Greenberg 1 [122]. Importantly, the shared deposition of CAA and LOAD Aβ may be one of the clearest representations of cross-talk between neurovascular and neurodegenerative mechanisms and the role of impaired Aβ clearance and EPVS. A definite diagnosis of CAA can only be confirmed through autopsy or surgical specimens; however, the Boston criteria are most often utilized in diagnosing CAA in living individuals Greenberg 2 [123].
Some of the molecular mechanisms that associate with CAA that are associated with the development and progression of LOAD include limitation of blood supply-cerebral hypoperfusion with decreased CBF, oxygen and nutrient deprivation instigating hypometabolism, increased OxRS and neuroinflammation, extravasation of cytokines/chemokines and neuroinflammation and activation of MMPs that degrade not only BBB TJ/AJ but also the BECs BMs with increased permeability that also increases the risk for cerebral hemorrhages with focal ischemia, OxRS, neuroinflammation and hemorrhagic complications acting as drivers for an increased in the development and progression of LOAD. [124].

7. Conclusions

While dementia is a more generalized term that describes the loss of the ability to think, remember, and reason to levels that interfere with daily life and activities, it can then be broken down into specific causes or disease. These specific diseases consist of four major types of dementia: (i) Alzheimer’s—LOAD-type dementia; (ii) vascular dementia (VaD) or co-occurring LOAD and VaD, resulting in mixed dementias (MDs), (iii) frontal temporal dementia, and (iv) Lewy body dementia [23].
Dr. Alois Alzheimer specifically described a 55-year-old female individual with dementia, which is typically now referred to as EOAD [125,126,127], in contrast to the global pandemic form of LOAD that has been the main focus of this narrative review. Thus, LOAD is expected to continue to grow nearly exponentially as the growing global population continues to age and experience longer life cycles, especially in the global post-World-War II baby boom generation (born between 1946–1964). This aging population will result in serious costs to national health care systems, government expenditures, as well as suffering for individuals, their families, professional health care providers, and long-term care facilities [6].
Importantly, VCID incorporates multiple cardio-cerebrovascular diseases, including cardiac disease and micro- and macrovessel disease both within the CNS and extracranial locations. Some now consider SVD to be a multisystem disorder [128]. VCID incorporates the heart-vascular-brain axis and includes vascular CNS injuries, such as clinical stroke, silent infarcts, microinfarcts, leukoaraiosis, cerebral amyloid angiopathy (CAA), transient ischemic attack(s) (TIAs), decreased cardiac output (as seen in myocardial infarction and congestive heart failure), and cardiac surgeries associated with decreased CBF and chronic cerebral hypoxia (CCH), as well as cerebral SVDs (lacunes, WMHs, EPVS, and CMBs), among others. This places VCID centrally in the overlapping Venn diagrams representing cardio-cerebrovascular disease and progressive cognitive impairment (Figure 21) [129].
The original amyloid cascade hypothesis has garnered the interest of most researchers, clinicians, and pharmaceutical companies over the past two decades [8,9]. Notably, Zlokovic proposed both a 2-hit vascular hypothesis [23] and a vasculo-neuronal-inflammatory triad model of neurodegenerative disorders in 2011 [130], which contributes to the development of neurodegeneration as found in LOAD and MD. Herein, the author currently proposes a ‘quartet of mechanisms’ that play a key role in the development of ND, LOAD, and MD in aging individuals. It can be compared to the triad of the vasculo-neuronal-inflammatory model proposed by Zlokovic and Griffin [130], which emphasizes oxidative redox stress in addition to the neurovascular mechanisms, including (i) oxidative redox stress (OxRS), (ii) neuroinflammation, (iii) neurovascular, and (iv) neurodegenerative mechanisms, in the development of LOAD and MD, as proposed when Figure 17, Figure 19 and Figure 21 are combined (Figure 22).
Recently, Ter Telgte et al. [131] have shown that there is a penumbra effect that may result in diffusion defects that associate with SVD phenotypes as observed on MRI images that is comparable to the penumbra effect associated with acute stroke and remodeling [132,133]. The post stroke penumbra is the viable tissue surrounding the irreversibly damaged ischemic core as in Figure 14C [132]. Further, they found that these focal effects were capable of spreading to become global effects at remote more distal regions within the CNS from the subcortical white matter regions to the cortical grey matter regions. As a result of their findings, it is now thought that the structural integrity may become dysfunctional and disrupted [131]. This could interrupt the brains network informational highway, potentially resulting in impaired cognition. This suggests that what we observe in MRI studies may only be the tip of the iceberg in terms of loss of function, impaired cognition, and aberrant motor skills, which may be concurrently affected, as depicted in Figure 21 and Figure 22, in the development of neurodegeneration, LOAD, VaD, and MD [131].
When studying chronic age-related diseases such as co-occurring VaD (including both arterial macrovessel and microvessel disease SVD), VaD, LOAD, and MD, it is important to understand microvessel SVD structural remodeling as a result of chronic, peripherally derived neurotoxic multiple injurious species. These changes relate to concurrent remodeling of arterioles, precapillary arterioles, the true capillary, the postcapillary venules and veins in development of vascular remodeling and microvessel SVD and neurodegeneration. Thus, it seems appropriate to pay homage to the microvessel SVD and specifically the component NVU cells in SVD. Given that the development of both microvessel SVD and LOAD are multifactorial, it is felt that it will require a multifactorial treatment approach.
The initiation of the microvessel SVD remodeling and neurodegeneration seems to continuously point to the importance of the early development of BECact/dys and BBBdd in the development of neurodegeneration. Furthermore, the combination of increased BEC inflammatory signaling, cnsCC production, decreased eNOS function with eNOS uncoupling, decreased NO, and increased OxRS from increased BEC NOX production, mt ROS leakage, and eNOS uncoupling, along with the brain endothelial-mediated neurotoxicity proposed by Grammas [134] as illustrated in Figure 2, contribute to decreased CBF and neurodegeneration, as shown in Figure 21 and Figure 22 [55].
This narrative review has examined the background of microvessel SVD development, highlighting not only its association with VaD but also with LOAD, which together contribute to the development of mixed dementia. MRI findings of SVD were compared in Box 2 of the introduction. Importantly, SVD may be considered as a series of clinical and imaging abnormalities on MRI, with pathological remodeling changes most commonly including CAA and arteriosclerosis/arteriolosclerosis [120]. The role of microvascular NVU and its constituent cells, especially the BECact/dys and BBBdd, was discussed in Section 2. Further, this allows leakage of peripheral neurotoxins into the CNS, resulting not only in the entry of pCC into the CNS but also the subsequent activation of cnsCC, promoting a state of neural OxRS as discussed in Section 3. Additionally, these mechanisms contribute to ongoing neuroinflammation, as presented in Section 4, and its relationship to neurodegeneration, as discussed in Section 5.

8. Future Directions

SVD not only contributes to the development of VAD, but also contributes to the pathogenesis of LOAD through various mechanisms, as discussed throughout this narrative review via the quartet of (i) neurovascular, (ii) OxRS, (iii) neuroinflammation, and (iv) neurodegenerative mechanisms. The developmental and pathobiological mechanisms of microvessel SVD and LOAD are both multifactorial. Therefore, the approach to treatment and future directions will most likely require a multifactorial and multifunctional treatment approach (Figure 23) [132,135,136,137].
While this narrative review has focused primarily on cerebral microvessel remodeling and SVD in the development of LOAD, it is important to also pay homage to the role of the systemic extracranial vascular system. Evidence collected from clinical and preclinical studies has demonstrated an intricate connection between extracranial atherosclerotic vascular disease in the peripheral circulation and BBB disruption of the NVU, with increased permeability [137]. This links systemic extracranial atherosclerosis to neurovascular remodeling and impairment of neurovascular integrity. Therefore, the author feels it is important to also explore this tight relationship between extracranial vascular disease and atherosclerosis, and apply interventions that might mitigate the increased risk of microvessel remodeling and SVD, in order to maintain cognitive abilities in our aging population.

Funding

The author has not received grants from any funding agency in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement

The tissues provided for the representative electron microscopic images utilized in this manuscript were all approved in advance by the University of Missouri Institutional Animal Care and Use Committee (No. 190; 7 July 2017). The animals were cared for in accordance with National Institutes of Health guidelines and by the Institutional Animal Care and Use Committees at the Harry S. Truman Memorial Veterans Hospital and the University of Missouri, Columbia, MO, USA, which conformed to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH).

Informed Consent Statement

Not applicable.

Data Availability Statement

The data and materials can be provided upon reasonable request.

Acknowledgments

The author would like to acknowledge Tatyana Shulyatnikova for the contribution of many artistic illustrations and editing of this manuscript. The author would also like to acknowledge DeAna Grant Research Specialist of the Electron Microscopy Core Facility at the Roy Blunt NextGen Precision Health Research Center, University of Missouri, Columbia, Missouri. The author also acknowledges the kind support of the William A. Banks Lab and Michelle Erickson at the VA Medical Center, Seattle, Washington.

Conflicts of Interest

The author declares no conflicts of interest.

Abbreviations

Aβ, amyloid beta; AC, astrocyte; ACef, astrocyte endfeet; BBB, blood–brain barrier; BEC(s), brain endothelial cell(s); BECact/dys, brain endothelial cell activation/dysfunction; BBBdd, blood–brain barrier dysfunction disruption; BDGF, brain-derived growth factor; bFGF, basic fibroblast growth factor; BM, basement membrane; CAA, cerebral amyloid angiopathy; CBF, cerebral blood flow; CL, capillary lumen; CMB(s), cerebral microbleeds; CNS, central nervous system; cnsCC, central nervous cytokines chemokines; ELOAD, early-onset Alzheimer’s disease; EPVS, enlarged perivascular spaces; ET-1, endothelin 1; GDNF, glia cell-derived growth factor; GS, glymphatic space; ISC, iron sulfur clusters; JAMs, junctional adhesion molecules; LOAD, late-onset Alzheimer’s disease; MCI, mild or minimal cognitive impairment; MD(s), mixed dementias; MGCs, microglia cells; MMP-2,-9, matrix metalloproteinase-2,-9; MRI, magnetic resonance imaging; mtROS, mitochondrial ROS; NADPH Ox, nicotine adenine diphosphate reduced oxidase; ND, neurodegeneration; NGF, nerve growth factor; NIH, National Institute of Health; NGTs, neurofibrillary tangles; NO, nitric oxide; NOX, NADPH oxidase, NVU, neurovascular unit; OxRS, oxidative redox stress; Pc, pericyte; pCC, peripheral cytokines chemokines; Pcfp, pericyte foot process; pvACfp/ef, perivascular astrocyte foot processes/endfeet; PVS, perivascular spaces; PVS/EPVS, perivascular space/enlarged perivascular space; ROS, reactive oxygen species, RONS, reactive oxygen, nitrogen species; RONSS, reactive oxygen, nitrogen, sulfur species; rPVACfp/ef, reactive perivascular astrocyte foot processes/endfeet; rPVMΦ, reactive resident perivascular macrophages; RSI, reactive species interactome; SVD, cerebral small vessel disease; TEM, transmission electron microscopy; TGFβ, transforming growth factor beta; TI/AJs, tight and adherens junctions; TNFα, tumor necrosis factor alpha; VaD, vascular dementia; VCAM-1, vascular cell adhesion molecule-1; VCID, vascular contributions to cognitive impairment and dementia; VEGF A or B, vascular endothelial growth factor A or B; VSMC(s), vascular smooth muscle cells; WMH, white matter hyperintensities.

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Figure 1. Representative transition electron microscopy (TEM) cross-section images of microvessels from various animal models from layer III of the frontal cortex at various magnifications. These images contrast with those of macrovessels that with a diameter measuring ≥5 μm and more than two layers of vascular smooth muscle cell(s) (VSMCs) within their media. Blue open arrows denote the basement membrane of the neurovascular unit in the true capillary. Magnification at 3 μm, 0.5 μm, 5 μm (far-left, middle, and far-right, respectively). Images provided with permission by CC 4.0 [1,2]. AC, astrocytes (pseudo-colored gold and blue in far-left and far-right images, respectively). AQP-4, aquaporin 4; AC, perivascular astrocyte; AC1, AC2, astrocyte endfeet numbers 1 and 2; ACef, perivascular astrocyte endfeet; CL, capillary lumen; EC, brain endothelial cell; gs, glymphatic space; lys, lysosome; Mt, mitochondria; N, nucleus; NVU, neurovascular unit; Pc, pericyte; PcN, pericyte nucleus; Pcp, pericyte endfeet processes; PVS, perivascular space; rMGC, interrogating or reactive microglia; rMΦ, reactive macrophage; TJ/AJ, tight junctions/adherens junctions.
Figure 1. Representative transition electron microscopy (TEM) cross-section images of microvessels from various animal models from layer III of the frontal cortex at various magnifications. These images contrast with those of macrovessels that with a diameter measuring ≥5 μm and more than two layers of vascular smooth muscle cell(s) (VSMCs) within their media. Blue open arrows denote the basement membrane of the neurovascular unit in the true capillary. Magnification at 3 μm, 0.5 μm, 5 μm (far-left, middle, and far-right, respectively). Images provided with permission by CC 4.0 [1,2]. AC, astrocytes (pseudo-colored gold and blue in far-left and far-right images, respectively). AQP-4, aquaporin 4; AC, perivascular astrocyte; AC1, AC2, astrocyte endfeet numbers 1 and 2; ACef, perivascular astrocyte endfeet; CL, capillary lumen; EC, brain endothelial cell; gs, glymphatic space; lys, lysosome; Mt, mitochondria; N, nucleus; NVU, neurovascular unit; Pc, pericyte; PcN, pericyte nucleus; Pcp, pericyte endfeet processes; PVS, perivascular space; rMGC, interrogating or reactive microglia; rMΦ, reactive macrophage; TJ/AJ, tight junctions/adherens junctions.
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Figure 2. Perivascular astrocyte endfeet (pvACef) provide the connections between the capillary and regional neurons to form the neurovascular unit (NVU). This combined cartoon illustration and transmission electron micrographs allows one to better visualize how the pvACef connect the NVU capillary to the regional neurons (A). Note that in panel (A) there is detachment and retraction of pvACef, which are noted in the diabetic db/db models. Other pvACef connect with the synapses (B). Modified images in panel (A,B) were provided with permission by CC 4.0 [16]. Asterisk, denotes emphasis; AC, astrocyte; ACef, astrocyte endfeet; AQP-4, aquaporin four; BDGF, brain derived growth factor; Ca++, calcium ion; CKC, control model; DBC, diabetic db/db model; DBE, diabetic db/db treated with empagliflozin; GDGF, glioma-derived growth factor; PSD, post synaptic density; S, synapse; TGF-β, transforming growth factor beta.
Figure 2. Perivascular astrocyte endfeet (pvACef) provide the connections between the capillary and regional neurons to form the neurovascular unit (NVU). This combined cartoon illustration and transmission electron micrographs allows one to better visualize how the pvACef connect the NVU capillary to the regional neurons (A). Note that in panel (A) there is detachment and retraction of pvACef, which are noted in the diabetic db/db models. Other pvACef connect with the synapses (B). Modified images in panel (A,B) were provided with permission by CC 4.0 [16]. Asterisk, denotes emphasis; AC, astrocyte; ACef, astrocyte endfeet; AQP-4, aquaporin four; BDGF, brain derived growth factor; Ca++, calcium ion; CKC, control model; DBC, diabetic db/db model; DBE, diabetic db/db treated with empagliflozin; GDGF, glioma-derived growth factor; PSD, post synaptic density; S, synapse; TGF-β, transforming growth factor beta.
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Figure 3. Multiple peripheral-systemic injurious species (neurotoxins) affect the brain endothelial cells (BECs) of the brain. These injurious species activate the BECs of the neurovascular unit (NVU), resulting in BEC activation and dysfunction (BECact/dys) and blood–brain barrier dysfunction/disruption (BBBdd). BECact/dys and BBBdd are biomarkers for the development of cerebral small vessel disease (SVD). Note the red-dashed line at the top of this image, which designates the location of the multiple injurious species that are responsible for initial brain endothelial cell injury in multiple clinical diseases and structural abnormalities, including SVD. BEC insulin resistance associated with an increase in glucose and the AGE receptor (RAGE) interaction is also important in the development of BECact/dys, BBBdd, and neurodegeneration (not shown). Image provided with permission by CC 4.0 [36,39]. AGE, advanced glycation end products; Ang II, angiotensin two; BBB, blood–brain barrier; BEC, brain endothelial cell; BBBdd, blood–brain barrier dysfunction and disruption; BECact/dys, brain endothelial cell activation/dysfunction; BH4, tetrahydrobiopterin; CCL2, chemokine (C-C motif) ligand 2; Cox-2, cyclo-oxygenase-2; Cox-2/PGE2 axis, cyclo-oxygenase-2/prostaglandin E2; ecGCx, endothelial glycocalyx; ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1β; IL-6, interleukin-6; JAMs, junctional adhesion molecules; LDL, low-density lipoprotein cholesterol; LPa, lipoprotein little a; MCP-1, monocyte chemotactic protein-1; NO, nitric oxide; Nox2, (NADPH Ox (nicotinamide adenine dinucleotide phosphate oxidase); ONOO-, peroxinitrite; pnsCC, peripheral nervous system cytokines and chemokines; NVU, neurovascular unit; RBC, red blood cell; Red arrows, denote increase; RONSS, reactive oxygen, nitrogen, sulfur species; ROS, reactive oxygen species; RSI, reactive species interactome; T, transcytosis; TNFα, tumor necrosis factor alpha; VCAM-1, vascular cellular adhesion molecule-1; WBC, white blood cell.
Figure 3. Multiple peripheral-systemic injurious species (neurotoxins) affect the brain endothelial cells (BECs) of the brain. These injurious species activate the BECs of the neurovascular unit (NVU), resulting in BEC activation and dysfunction (BECact/dys) and blood–brain barrier dysfunction/disruption (BBBdd). BECact/dys and BBBdd are biomarkers for the development of cerebral small vessel disease (SVD). Note the red-dashed line at the top of this image, which designates the location of the multiple injurious species that are responsible for initial brain endothelial cell injury in multiple clinical diseases and structural abnormalities, including SVD. BEC insulin resistance associated with an increase in glucose and the AGE receptor (RAGE) interaction is also important in the development of BECact/dys, BBBdd, and neurodegeneration (not shown). Image provided with permission by CC 4.0 [36,39]. AGE, advanced glycation end products; Ang II, angiotensin two; BBB, blood–brain barrier; BEC, brain endothelial cell; BBBdd, blood–brain barrier dysfunction and disruption; BECact/dys, brain endothelial cell activation/dysfunction; BH4, tetrahydrobiopterin; CCL2, chemokine (C-C motif) ligand 2; Cox-2, cyclo-oxygenase-2; Cox-2/PGE2 axis, cyclo-oxygenase-2/prostaglandin E2; ecGCx, endothelial glycocalyx; ICAM-1, intercellular adhesion molecule-1; IL-1β, interleukin-1β; IL-6, interleukin-6; JAMs, junctional adhesion molecules; LDL, low-density lipoprotein cholesterol; LPa, lipoprotein little a; MCP-1, monocyte chemotactic protein-1; NO, nitric oxide; Nox2, (NADPH Ox (nicotinamide adenine dinucleotide phosphate oxidase); ONOO-, peroxinitrite; pnsCC, peripheral nervous system cytokines and chemokines; NVU, neurovascular unit; RBC, red blood cell; Red arrows, denote increase; RONSS, reactive oxygen, nitrogen, sulfur species; ROS, reactive oxygen species; RSI, reactive species interactome; T, transcytosis; TNFα, tumor necrosis factor alpha; VCAM-1, vascular cellular adhesion molecule-1; WBC, white blood cell.
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Figure 4. Brain endothelial cell activation and dysfunction (BECact/dys) phenotypes in obese 20-week-old female diabetic db/db models. (A,B) demonstrate normal control phenotypes of microvessel neurovascular unit (NVU) BEC from control C57B5J model at 20 weeks in the frontal cortical layer III in cross and longitudinal sections (A,B), respectively. Note that the perivascular astrocytes are pseudo-colored golden with apparently normal electron-dense mitochondria. Also note the cyan-colored line that demarcates the glia limitans in (A,B). (C) demonstrates the control normal phenotype in the C57B6J model at 20 weeks. (D) depicts an activated BEC with marked abrupt swelling of the BEC that is hyperlucent as compared to the adjacent normal thickness of the BEC, which depicts BECact/dys phenotype in the 20-week-old db/db model from the frontal cortex of layer III. (E) depicts the BM thickening of BECs in (D). Note the vacuole-like structures (V) within the BM. (F) through (I) depict the adhesion of monocyte (F), a lymphocyte (G), a platelet (H), and a red blood cell (RBC) (I). Modified images provided with permission by CC 4.0 [2,39,40,41]. AC, astrocyte; ACfp, astrocyte foot process endfeet; BM, basement membrane; Cap L, capillary lumen; CL, capillary lumen; ECact, brain endothelial cell activation; iMGC, interrogating microglia cell; Mt, mitochondria; Mp, microparticles; Pc, pericyte; Red arrows, denote BEC activation; White arrows, denote RBC adhesion plaques; Yellow arrows, denote platelet.
Figure 4. Brain endothelial cell activation and dysfunction (BECact/dys) phenotypes in obese 20-week-old female diabetic db/db models. (A,B) demonstrate normal control phenotypes of microvessel neurovascular unit (NVU) BEC from control C57B5J model at 20 weeks in the frontal cortical layer III in cross and longitudinal sections (A,B), respectively. Note that the perivascular astrocytes are pseudo-colored golden with apparently normal electron-dense mitochondria. Also note the cyan-colored line that demarcates the glia limitans in (A,B). (C) demonstrates the control normal phenotype in the C57B6J model at 20 weeks. (D) depicts an activated BEC with marked abrupt swelling of the BEC that is hyperlucent as compared to the adjacent normal thickness of the BEC, which depicts BECact/dys phenotype in the 20-week-old db/db model from the frontal cortex of layer III. (E) depicts the BM thickening of BECs in (D). Note the vacuole-like structures (V) within the BM. (F) through (I) depict the adhesion of monocyte (F), a lymphocyte (G), a platelet (H), and a red blood cell (RBC) (I). Modified images provided with permission by CC 4.0 [2,39,40,41]. AC, astrocyte; ACfp, astrocyte foot process endfeet; BM, basement membrane; Cap L, capillary lumen; CL, capillary lumen; ECact, brain endothelial cell activation; iMGC, interrogating microglia cell; Mt, mitochondria; Mp, microparticles; Pc, pericyte; Red arrows, denote BEC activation; White arrows, denote RBC adhesion plaques; Yellow arrows, denote platelet.
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Figure 5. Proinflammatory LPS results in attenuation and discontinuous endothelial glycocalyx (ecGCx) and increased pinocytosis/transcytosis in activated brain endothelial cell activation/dysfunction (BECact/dys). Far-left panels (B,D) depict an attenuation and discontinuous ecGCx with large gaps of BECs as compared to controls with an intact and continuous ecGCx, as in panels (A,C). Far-right panels (B,D) depict increased pinocytosis/transcytosis of BEC as compared to control panels (A,C). Panels (C,D) are illustrations to improve and highlight the findings of the TEMs depicted in panels (A,B). Images provided with permission by CC 4.0 [42]. Asterisks, denote macropinocytosis; ACfp, astrocyte foot process endfeet; atMGC, attracted microglia cell(s); BECact/dys, brain endothelial cell activation/dysfunction; CL, capillary lumen; ecGCx, brain endothelial cell glycocalyx; EC N, brain endothelial cell nucleus; LPS, lipopolysaccharide; Pc N, pericyte nucleus; PVS, perivascular space; TJ/AJ, tight and adherence junctions.
Figure 5. Proinflammatory LPS results in attenuation and discontinuous endothelial glycocalyx (ecGCx) and increased pinocytosis/transcytosis in activated brain endothelial cell activation/dysfunction (BECact/dys). Far-left panels (B,D) depict an attenuation and discontinuous ecGCx with large gaps of BECs as compared to controls with an intact and continuous ecGCx, as in panels (A,C). Far-right panels (B,D) depict increased pinocytosis/transcytosis of BEC as compared to control panels (A,C). Panels (C,D) are illustrations to improve and highlight the findings of the TEMs depicted in panels (A,B). Images provided with permission by CC 4.0 [42]. Asterisks, denote macropinocytosis; ACfp, astrocyte foot process endfeet; atMGC, attracted microglia cell(s); BECact/dys, brain endothelial cell activation/dysfunction; CL, capillary lumen; ecGCx, brain endothelial cell glycocalyx; EC N, brain endothelial cell nucleus; LPS, lipopolysaccharide; Pc N, pericyte nucleus; PVS, perivascular space; TJ/AJ, tight and adherence junctions.
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Figure 6. Loss and/or disruption of the normal continuous tight and adherence junction(s) (TJ/AJs) paracellular blood–brain barrier (BBB) in male CD-1 streptozotocin-induced (STZ) diabetic preclinical mice models, resulting in blood–brain barrier dysfunction and disruption (BBBdd) protected by the carbonic anhydrase inhibitor (topiramate, a mitochondria-specific antioxidant) in the midbrain as compared to the cerebellum. STZ-induced diabetic mice revealed disruption of the BBB by 14C-sucrose measurements. Panel (A) displays three prominent elongated and continuous highly electron-dense TJ/AJ (white and black arrows). Panel (B) depicts a discontinuous and disrupted TJ/AJ (black arrows) into three distinct segments in the midbrain of STZ-induced diabetic models. Note how TJ/AJs tend to form at the BEC-BEC overlap junctions in panels (AC). Panel (C) illustrates that treatment with topiramate (TOP) prevented disruption in the brain endothelial cell BBB (yellow and black arrows and yellow dashed line below the intact BBB TJ/AJ) in the midbrain. Revised figure images provided with permission by CC 4.0 [39,42,43]. Magnification ×3000; scale bar = 0.5 μm (A); ×10,000; scale bar = 0.2 μm in (B,C). BEC, brain endothelial cell; EC, brain endothelial cell; CL, capillary lumen; Pc, pericyte; RBC, red blood cell; Rx, treatment; T1DM, type 1 diabetes mellitus; TOP, topiramate; White arrows, denote brain endothelial cell.
Figure 6. Loss and/or disruption of the normal continuous tight and adherence junction(s) (TJ/AJs) paracellular blood–brain barrier (BBB) in male CD-1 streptozotocin-induced (STZ) diabetic preclinical mice models, resulting in blood–brain barrier dysfunction and disruption (BBBdd) protected by the carbonic anhydrase inhibitor (topiramate, a mitochondria-specific antioxidant) in the midbrain as compared to the cerebellum. STZ-induced diabetic mice revealed disruption of the BBB by 14C-sucrose measurements. Panel (A) displays three prominent elongated and continuous highly electron-dense TJ/AJ (white and black arrows). Panel (B) depicts a discontinuous and disrupted TJ/AJ (black arrows) into three distinct segments in the midbrain of STZ-induced diabetic models. Note how TJ/AJs tend to form at the BEC-BEC overlap junctions in panels (AC). Panel (C) illustrates that treatment with topiramate (TOP) prevented disruption in the brain endothelial cell BBB (yellow and black arrows and yellow dashed line below the intact BBB TJ/AJ) in the midbrain. Revised figure images provided with permission by CC 4.0 [39,42,43]. Magnification ×3000; scale bar = 0.5 μm (A); ×10,000; scale bar = 0.2 μm in (B,C). BEC, brain endothelial cell; EC, brain endothelial cell; CL, capillary lumen; Pc, pericyte; RBC, red blood cell; Rx, treatment; T1DM, type 1 diabetes mellitus; TOP, topiramate; White arrows, denote brain endothelial cell.
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Figure 7. Brain pericyte(s) (Pcs) and brain endothelial cell(s) (BECs) are closely interconnected and are interdependent for paracrine signaling, making the Pc a critical cell for proper homeostatic function of the neurovascular unit(s) (NVU) in controlling regional cerebral blood flow (CBF). Panel (A) demonstrates the normal arrangement of the BEC, Pc, and perivascular astrocyte endfeet (pvACef). Note how the basement membrane (black open arrows) is interspersed and separates the luminal BEC, Pc, and the more abluminal pvACef. Also note the interrogating microglia cell (iMGC) (white closed arrow). Panel (B) illustrates with better clarity the close interactions between the Pc and the BEC (EC), which importantly allows for paracrine signaling as well as structural and functional support by the NVUs. Panel (C) illustrates the paracrine signaling of nitric oxide (NO) synthesized by the eNOS enzyme to signal the Pc cell to relax, allowing for vasodilation and the supportive connection by the platelet-derived growth factor beta (PDGFβ) of the EC to interact with the PDGFβ receptor (PDGFβ R) of the adjacent Pc. Images provided with permission by CC 4.0 [44,45]. ACef, astrocyte endfeet; AQP4, aquaporin 4; PcP, pericyte processes-endfeet-foot processes; N, nucleus; TJ/AJ, tight and adherens junctions; VEGF A-B, vascular endothelial growth factor A-B; VEGF R, receptor for VEGF.
Figure 7. Brain pericyte(s) (Pcs) and brain endothelial cell(s) (BECs) are closely interconnected and are interdependent for paracrine signaling, making the Pc a critical cell for proper homeostatic function of the neurovascular unit(s) (NVU) in controlling regional cerebral blood flow (CBF). Panel (A) demonstrates the normal arrangement of the BEC, Pc, and perivascular astrocyte endfeet (pvACef). Note how the basement membrane (black open arrows) is interspersed and separates the luminal BEC, Pc, and the more abluminal pvACef. Also note the interrogating microglia cell (iMGC) (white closed arrow). Panel (B) illustrates with better clarity the close interactions between the Pc and the BEC (EC), which importantly allows for paracrine signaling as well as structural and functional support by the NVUs. Panel (C) illustrates the paracrine signaling of nitric oxide (NO) synthesized by the eNOS enzyme to signal the Pc cell to relax, allowing for vasodilation and the supportive connection by the platelet-derived growth factor beta (PDGFβ) of the EC to interact with the PDGFβ receptor (PDGFβ R) of the adjacent Pc. Images provided with permission by CC 4.0 [44,45]. ACef, astrocyte endfeet; AQP4, aquaporin 4; PcP, pericyte processes-endfeet-foot processes; N, nucleus; TJ/AJ, tight and adherens junctions; VEGF A-B, vascular endothelial growth factor A-B; VEGF R, receptor for VEGF.
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Figure 8. Pericyte endfeet (Pcef) retraction and pericyte nucleus (Pc N) rounding are early signs of Pc dysfunction, along with the formation of aberrant mitochondria (aMt), which are found in brain endothelial cells (ECs), Pcs, astrocyte(s) (ACs), neuronal axons, and oligodendrocytes (OLIG) along with Pc cytoplasmic apoptotic changes with apoptotic bodies. Panels (13) illustrate Pc N rounding and retraction of Pcef in panels (2 and 3) as compared to control model Pc N elongation and elongation of Pcef (pseudo-colored green) in panel 1. Panels (AE) depict aberrant mitochondria (aMt) in BECs, ACs, Pcef, neuronal axons, and oligodendrocytes (OLIG), respectively. Panel (F) depicts an apoptotic Pc with numerous apoptotic bodies observed in this Pc cytoplasm (arrows), which are indicative of Pc degeneration and death. Scale bars vary and are included in the images presented. Modified images provided with permission by CC 4.0 [59,60,61]. Asterisk, denotes emphasis; BEC, brain endothelial cell; CL, capillary lumen; EC, endothelial cell-brain endothelial cell; N, nucleus; Pc, pericyte; RBC, red blood cell.
Figure 8. Pericyte endfeet (Pcef) retraction and pericyte nucleus (Pc N) rounding are early signs of Pc dysfunction, along with the formation of aberrant mitochondria (aMt), which are found in brain endothelial cells (ECs), Pcs, astrocyte(s) (ACs), neuronal axons, and oligodendrocytes (OLIG) along with Pc cytoplasmic apoptotic changes with apoptotic bodies. Panels (13) illustrate Pc N rounding and retraction of Pcef in panels (2 and 3) as compared to control model Pc N elongation and elongation of Pcef (pseudo-colored green) in panel 1. Panels (AE) depict aberrant mitochondria (aMt) in BECs, ACs, Pcef, neuronal axons, and oligodendrocytes (OLIG), respectively. Panel (F) depicts an apoptotic Pc with numerous apoptotic bodies observed in this Pc cytoplasm (arrows), which are indicative of Pc degeneration and death. Scale bars vary and are included in the images presented. Modified images provided with permission by CC 4.0 [59,60,61]. Asterisk, denotes emphasis; BEC, brain endothelial cell; CL, capillary lumen; EC, endothelial cell-brain endothelial cell; N, nucleus; Pc, pericyte; RBC, red blood cell.
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Figure 9. Neurotoxicity of amyloid beta in close proximity to the neurovascular unit (NVU) brain endothelial cell(s) (BECs) may result in blood–brain barrier dysfunction and disruption (BBBdd). These images are from a 9-month-old 5xFAD male mouse model not previously published. Panel (A) depicts interstitial extracellular matrix-interstitial amyloid beta (Aβ) (pseudo-colored red) in close proximity to the NVU, which appears to nearly touch the outer basement membrane (BM) of the NVU depicted. Importantly, note that this image depicts degenerative neurites (yellow arrows and outlined in yellow dashed-lines) within the adjacent interstitial neuropil. Panel (B) depicts an exploded image in Microsoft paint with an intact scale bar. Insert (C) is a further exploded image demonstrating how Aβ is closely adjacent to the microvessel NVU BEC basement membrane (BM) (open red and white arrows) and appears to actually be in direct contact with the BM. Indeed, this structural arrangement contributes to Aβ being neurotoxic to BECs and creating a vicious cycle of BEC injury by Aβ and BECact/dys that contributes to a further increase in ROS and damage to the NVU, with eventual NVU uncoupling and a decrease in regional cerebral blood flow. This will ultimately increase neurodegeneration and increase or accelerate amyloid beta deposition.
Figure 9. Neurotoxicity of amyloid beta in close proximity to the neurovascular unit (NVU) brain endothelial cell(s) (BECs) may result in blood–brain barrier dysfunction and disruption (BBBdd). These images are from a 9-month-old 5xFAD male mouse model not previously published. Panel (A) depicts interstitial extracellular matrix-interstitial amyloid beta (Aβ) (pseudo-colored red) in close proximity to the NVU, which appears to nearly touch the outer basement membrane (BM) of the NVU depicted. Importantly, note that this image depicts degenerative neurites (yellow arrows and outlined in yellow dashed-lines) within the adjacent interstitial neuropil. Panel (B) depicts an exploded image in Microsoft paint with an intact scale bar. Insert (C) is a further exploded image demonstrating how Aβ is closely adjacent to the microvessel NVU BEC basement membrane (BM) (open red and white arrows) and appears to actually be in direct contact with the BM. Indeed, this structural arrangement contributes to Aβ being neurotoxic to BECs and creating a vicious cycle of BEC injury by Aβ and BECact/dys that contributes to a further increase in ROS and damage to the NVU, with eventual NVU uncoupling and a decrease in regional cerebral blood flow. This will ultimately increase neurodegeneration and increase or accelerate amyloid beta deposition.
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Figure 10. Astrocyte(s) (ACs) are the master communication/connecting cell(s) (CCC) within the brain universe. This collection of illustrations and transmission electron microscopy (TEM) images demonstrates the CCC functions of ACs through their various perivascular, perisynaptic, perineuronal endfeet, and cell-cell junctions (inserts 1–5). Insert 1 demonstrates the important role of perivascular astrocyte endfeet (pvACef; pseudo-colored golden) communication/connection. Note how this communicating/connecting AC allows for neurovascular coupling with regional neurons (insert 3) in frontal cortex layer III in control mice at 20 weeks of age. Insert 2 illustrates the communication/connection of the astrocyte perisynaptic endfeet (psACef) (pseudo-colored yellow). Insert 3 illustrates the communication/connection of ACs to myelinated and unmyelinated neurons. Insert 4 depicts the lost connections between a reactive microglial cell (rMGC) (pseudo-colored blue with nuclear chromatin condensation) and multiple reactive, detached, and separated ACs (pseudo-colored red) adjacent to a neurovascular unit (NVU) with a single intact non-reactive AC (pseudo-colored yellow) in the diabetic db/db model cortical layer III at 20 weeks of age. Insert 5 illustrates AC-to-AC connections in cortical layer III in control models (hand-drawn computer-assisted illustration of light microscopic toluidine blue stained images from control C57BL/6J models) via gap junction connexins (Cx43). Inserts 1–4 have scale bars of 0.5 μm, 100 nm, 1 μm, and 2 μm, respectively. The background image represents a hand-drawn computer-assisted image derived from control C57BL/6J toluidine blue stained models and does not have a scale bar. This highly modified image is provided with permission by CC 4.0 [16]. ACfp, protoplasmic perivascular astrocyte endfeet; ACPVef, astrocyte perivascular endfeet; Cap L, capillary lumen; EC, brain endothelial cell; iMGC, interrogating microglial cell; Mt, mitochondria; N, nucleus; Pc, pericyte; PSD, post-synaptic density; PVACef, perivascular astrocyte endfeet; rMGC, reactive microglia cell; psACef, perisynaptic astrocyte endfeet.
Figure 10. Astrocyte(s) (ACs) are the master communication/connecting cell(s) (CCC) within the brain universe. This collection of illustrations and transmission electron microscopy (TEM) images demonstrates the CCC functions of ACs through their various perivascular, perisynaptic, perineuronal endfeet, and cell-cell junctions (inserts 1–5). Insert 1 demonstrates the important role of perivascular astrocyte endfeet (pvACef; pseudo-colored golden) communication/connection. Note how this communicating/connecting AC allows for neurovascular coupling with regional neurons (insert 3) in frontal cortex layer III in control mice at 20 weeks of age. Insert 2 illustrates the communication/connection of the astrocyte perisynaptic endfeet (psACef) (pseudo-colored yellow). Insert 3 illustrates the communication/connection of ACs to myelinated and unmyelinated neurons. Insert 4 depicts the lost connections between a reactive microglial cell (rMGC) (pseudo-colored blue with nuclear chromatin condensation) and multiple reactive, detached, and separated ACs (pseudo-colored red) adjacent to a neurovascular unit (NVU) with a single intact non-reactive AC (pseudo-colored yellow) in the diabetic db/db model cortical layer III at 20 weeks of age. Insert 5 illustrates AC-to-AC connections in cortical layer III in control models (hand-drawn computer-assisted illustration of light microscopic toluidine blue stained images from control C57BL/6J models) via gap junction connexins (Cx43). Inserts 1–4 have scale bars of 0.5 μm, 100 nm, 1 μm, and 2 μm, respectively. The background image represents a hand-drawn computer-assisted image derived from control C57BL/6J toluidine blue stained models and does not have a scale bar. This highly modified image is provided with permission by CC 4.0 [16]. ACfp, protoplasmic perivascular astrocyte endfeet; ACPVef, astrocyte perivascular endfeet; Cap L, capillary lumen; EC, brain endothelial cell; iMGC, interrogating microglial cell; Mt, mitochondria; N, nucleus; Pc, pericyte; PSD, post-synaptic density; PVACef, perivascular astrocyte endfeet; rMGC, reactive microglia cell; psACef, perisynaptic astrocyte endfeet.
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Figure 11. A master communicating, connecting, and signaling cell of the brain universe providing homeostasis. In addition to being neuroprotective, astrocytes provide molecular, cellular, and network communication, as well as systemic, metabolic, and whole organ homeostasis. The centrally located modified image of an astrocyte from Figure 10 was provided with permission by CC 4.0 [16]. AC, astrocyte; ACef, astrocyte endfeet; AQP4, aquaporin-4; BBB, blood–brain barrier; Ca++, calcium; Cap L, capillary lumen; CBF, cerebral blood flow; Cl-, chloride; CNS, central nervous system; CO2, carbon monoxide; EC, brain endothelial cell; GABA, gamma aminobutyric acid; K+, potassium; Na+, sodium; NVU, neurovascular unit; PVACef, perivascular astrocyte endfeet; rMGC, reactive microglia cell.
Figure 11. A master communicating, connecting, and signaling cell of the brain universe providing homeostasis. In addition to being neuroprotective, astrocytes provide molecular, cellular, and network communication, as well as systemic, metabolic, and whole organ homeostasis. The centrally located modified image of an astrocyte from Figure 10 was provided with permission by CC 4.0 [16]. AC, astrocyte; ACef, astrocyte endfeet; AQP4, aquaporin-4; BBB, blood–brain barrier; Ca++, calcium; Cap L, capillary lumen; CBF, cerebral blood flow; Cl-, chloride; CNS, central nervous system; CO2, carbon monoxide; EC, brain endothelial cell; GABA, gamma aminobutyric acid; K+, potassium; Na+, sodium; NVU, neurovascular unit; PVACef, perivascular astrocyte endfeet; rMGC, reactive microglia cell.
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Figure 12. Reactive microglia cell(s) (rMGCs) and astrocyte(s) (rACs) contribute to Ddecreased cerebral blood flow and neurodegeneration (ND). Panel (A) demonstrates a normal neurovascular unit (NVU) with its normal interrogating MGC (iMGC) (pseudo-colored green) and its intact astrocytes (iAC) (pseudo-colored golden). Panel (B) depicts a prominent rMGC invading the NVU (pseudo-colored red). Note the aberrant mitochondria (aMt) (pseudo-colored yellow and outlined in red). Notably, the normal iAC have become detached and retracted, separated (drAC, pseudo-colored light blue) from the NVU outer basement membrane and results in NVU uncoupling, with ensuing decreased cerebral blood flow to regional neurons resulting in hypometabolism, hypoperfusion, regional neuronal hypoxia/ischemia with subsequent neurodegeneration, and impaired cognition. Modified images provided with permission by CC 4.0 [6,60]. CL, capillary lumen; drAC, detached reactive, retracted astrocyte endfeet; N, nucleus; RBC, red blood cell.
Figure 12. Reactive microglia cell(s) (rMGCs) and astrocyte(s) (rACs) contribute to Ddecreased cerebral blood flow and neurodegeneration (ND). Panel (A) demonstrates a normal neurovascular unit (NVU) with its normal interrogating MGC (iMGC) (pseudo-colored green) and its intact astrocytes (iAC) (pseudo-colored golden). Panel (B) depicts a prominent rMGC invading the NVU (pseudo-colored red). Note the aberrant mitochondria (aMt) (pseudo-colored yellow and outlined in red). Notably, the normal iAC have become detached and retracted, separated (drAC, pseudo-colored light blue) from the NVU outer basement membrane and results in NVU uncoupling, with ensuing decreased cerebral blood flow to regional neurons resulting in hypometabolism, hypoperfusion, regional neuronal hypoxia/ischemia with subsequent neurodegeneration, and impaired cognition. Modified images provided with permission by CC 4.0 [6,60]. CL, capillary lumen; drAC, detached reactive, retracted astrocyte endfeet; N, nucleus; RBC, red blood cell.
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Figure 13. Enlarged perivascular space (EPVS) and resident-reactive perivascular macrophage (rPVMΦs) in a postcapillary venule compared to a true capillary. Panel (A) demonstrates a normal true capillary in a 20-week-old female C57B6/J control model. Note how the astrocyte endfeet (ACef) tightly abut the shared basement membrane (open black arrows) of the brain endothelial cell (BEC) and pericyte foot process (PcP). Panel (B) depicts an EPVS with a prominent rPVMΦ (pseudo-colored red) in a 20-week-old lipopolysaccharide (LPS)-treated CD-1 male mouse model. Note how the ACfp are markedly separated from the capillary mural cells (BEC and Pc) (red double arrows). Panel (C) depicts the rPVMΦs in an exploded image with intimate contact with the Pcfps basal lamina, as well as its intimate contact with the basal lamina of the ACef (outermost boundary of the EPVS abluminal lining) (dashed blue circles). Modified images provided with permission by CC 4.0 [45]. AQP4, aquaporin 4; Lys, lysosomes; Mt, mitochondria; N, nucleus; NVU, neurovascular unit; V, vacuoles; ves, vesicles.
Figure 13. Enlarged perivascular space (EPVS) and resident-reactive perivascular macrophage (rPVMΦs) in a postcapillary venule compared to a true capillary. Panel (A) demonstrates a normal true capillary in a 20-week-old female C57B6/J control model. Note how the astrocyte endfeet (ACef) tightly abut the shared basement membrane (open black arrows) of the brain endothelial cell (BEC) and pericyte foot process (PcP). Panel (B) depicts an EPVS with a prominent rPVMΦ (pseudo-colored red) in a 20-week-old lipopolysaccharide (LPS)-treated CD-1 male mouse model. Note how the ACfp are markedly separated from the capillary mural cells (BEC and Pc) (red double arrows). Panel (C) depicts the rPVMΦs in an exploded image with intimate contact with the Pcfps basal lamina, as well as its intimate contact with the basal lamina of the ACef (outermost boundary of the EPVS abluminal lining) (dashed blue circles). Modified images provided with permission by CC 4.0 [45]. AQP4, aquaporin 4; Lys, lysosomes; Mt, mitochondria; N, nucleus; NVU, neurovascular unit; V, vacuoles; ves, vesicles.
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Figure 14. Multipotential reactive astrocyte (rAC) phenotype remodeling in late-onset Alzheimer’s disease (LOAD) from hypertrophy to atrophy. Panel (A) depicts extracellular matrix interstitial space amyloid beta (Aβ) plaques that are increased in LOAD and co-occur with soluble Aβ oligomers, which are actually more neurotoxic than the Aβ mature plaques. Panel (B) lists the components of Aβ plaques (1.-5.). Panel (CI) demonstrates the remodeling of the rACs that follows such injuries as ischemic or hemorrhagic stroke with palisading and hypertrophic phenotypes in contrast to the rAC phenotype of atrophy, which is associated with AC remodeling due to the neurotoxicity of Aβ oligomers and Aβ extracellular plaque aggregation, as discussed in (CII). Modified images of Aβ in panel (A) are provided with permission by CC 4.0 [74] and the reproduced image in C1 is provided with permission by CC 4.0 [28,75]. ApoE, apolipoprotein E; CNS, central nervous system; cnsCC, central nervous system cytokines/chemokines; DNA, deoxyribonucleic acid; GAGS, glycosaminoglycans; LOAD, late-onset Alzheimer’s disease; MMP(s), matrix metalloproteinases; PGN, proteoglycan(s); rAC(s), reactive astrocytes; ROI, region of interest; rMGC(s), reactive microglia cells; ROS, reactive oxygen species; RNA, ribonucleic acid.
Figure 14. Multipotential reactive astrocyte (rAC) phenotype remodeling in late-onset Alzheimer’s disease (LOAD) from hypertrophy to atrophy. Panel (A) depicts extracellular matrix interstitial space amyloid beta (Aβ) plaques that are increased in LOAD and co-occur with soluble Aβ oligomers, which are actually more neurotoxic than the Aβ mature plaques. Panel (B) lists the components of Aβ plaques (1.-5.). Panel (CI) demonstrates the remodeling of the rACs that follows such injuries as ischemic or hemorrhagic stroke with palisading and hypertrophic phenotypes in contrast to the rAC phenotype of atrophy, which is associated with AC remodeling due to the neurotoxicity of Aβ oligomers and Aβ extracellular plaque aggregation, as discussed in (CII). Modified images of Aβ in panel (A) are provided with permission by CC 4.0 [74] and the reproduced image in C1 is provided with permission by CC 4.0 [28,75]. ApoE, apolipoprotein E; CNS, central nervous system; cnsCC, central nervous system cytokines/chemokines; DNA, deoxyribonucleic acid; GAGS, glycosaminoglycans; LOAD, late-onset Alzheimer’s disease; MMP(s), matrix metalloproteinases; PGN, proteoglycan(s); rAC(s), reactive astrocytes; ROI, region of interest; rMGC(s), reactive microglia cells; ROS, reactive oxygen species; RNA, ribonucleic acid.
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Figure 15. Aberrant mitochondria (aMt) allow for leaky prooxidative ROS of the reactive species interactome (RSI) and prooxidative iron sulfur cluster(s) (ISCs) to enter the cytosol with dysfunction and damage to the cell and surrounding cells. Note how the aMt remodeling appears as compared to the normal control insert upper left with its hyperlucency, crista fragmentation and loss, loss of electron dense mitochondrial matrix, and permeabilization of the outer mitochondria membrane (asterisk). This permeabilization allows the redox-active and prooxidative mtROS and iron sulfur clusters to escape into the cellular cytosol resulting in cellular dysfunction, damage and even apoptosis. This prooxidant mechanism has an increased impact if the antioxidant reserves of super oxide dismutase (SOD), catalase, and glutathione (GSH) have previously been or are currently depleted. Revised background image of the aMt is provided with permission by CC 4.0 [61]. aMt, aberrant mitochondria; Cys, cysteine; ETC, electron transport chain; Fe, iron; ISC, iron sulfur cluster(s); MOMP, mitochondrial outer membrane permeabilization; Mt, mitochondria; mtROS, mitochondrial-derived reactive oxygen species; RONSS, reactive oxygen, nitrogen, sulfur species; S, sulfur.
Figure 15. Aberrant mitochondria (aMt) allow for leaky prooxidative ROS of the reactive species interactome (RSI) and prooxidative iron sulfur cluster(s) (ISCs) to enter the cytosol with dysfunction and damage to the cell and surrounding cells. Note how the aMt remodeling appears as compared to the normal control insert upper left with its hyperlucency, crista fragmentation and loss, loss of electron dense mitochondrial matrix, and permeabilization of the outer mitochondria membrane (asterisk). This permeabilization allows the redox-active and prooxidative mtROS and iron sulfur clusters to escape into the cellular cytosol resulting in cellular dysfunction, damage and even apoptosis. This prooxidant mechanism has an increased impact if the antioxidant reserves of super oxide dismutase (SOD), catalase, and glutathione (GSH) have previously been or are currently depleted. Revised background image of the aMt is provided with permission by CC 4.0 [61]. aMt, aberrant mitochondria; Cys, cysteine; ETC, electron transport chain; Fe, iron; ISC, iron sulfur cluster(s); MOMP, mitochondrial outer membrane permeabilization; Mt, mitochondria; mtROS, mitochondrial-derived reactive oxygen species; RONSS, reactive oxygen, nitrogen, sulfur species; S, sulfur.
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Figure 16. Reactive oxygen species (ROS) instigates ROS and oxidative-redox stress (OxRS) in a vicious cycle with neuroinflammation. This vicious cycle contributes to impaired cognition and neurodegeneration. Metabolic and hormonal excesses in addition to injury-trauma and the vicious cycle of neuroinflammation and ROS—OxRS lead to blood–brain barrier dysfunction and disruption with NVU uncoupling and regional hypometabolism and ischemia/ischemia reperfusion injury result in a cascade to neurodegeneration and brain atrophy with impaired cognition that associates with late-onset Alzheimer’s disease (LOAD). Modified figure provided with permission by CC 4.0 [28,36,85]. AGE/RAGE, advanced glycation end products/receptor for advanced glycation end products; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; BH4, tetrahydrobiopterin; eNOS, endothelial nitric oxide synthase; FFA, free fatty acids; HPA, hypothalamic pituitary adrenal; I-CAM, intercellular adhesion molecule; MC, mast cell; MGCs, microglia cells; NADPH—NADPH Ox, reduced nicotinamide adenine dinucleotide phosphate oxidase; NVU. neurovascular unit; NF-kB, nuclear factor- kappa B; RAS, renin angiotensin system; RAAS, renin angiotensin aldosterone system; ROS/RNS, reactive oxygen species/reactive nitrogen species. UV, ultraviolet; VE-CAM, vascular endothelial cellular adhesion molecule.
Figure 16. Reactive oxygen species (ROS) instigates ROS and oxidative-redox stress (OxRS) in a vicious cycle with neuroinflammation. This vicious cycle contributes to impaired cognition and neurodegeneration. Metabolic and hormonal excesses in addition to injury-trauma and the vicious cycle of neuroinflammation and ROS—OxRS lead to blood–brain barrier dysfunction and disruption with NVU uncoupling and regional hypometabolism and ischemia/ischemia reperfusion injury result in a cascade to neurodegeneration and brain atrophy with impaired cognition that associates with late-onset Alzheimer’s disease (LOAD). Modified figure provided with permission by CC 4.0 [28,36,85]. AGE/RAGE, advanced glycation end products/receptor for advanced glycation end products; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; BH4, tetrahydrobiopterin; eNOS, endothelial nitric oxide synthase; FFA, free fatty acids; HPA, hypothalamic pituitary adrenal; I-CAM, intercellular adhesion molecule; MC, mast cell; MGCs, microglia cells; NADPH—NADPH Ox, reduced nicotinamide adenine dinucleotide phosphate oxidase; NVU. neurovascular unit; NF-kB, nuclear factor- kappa B; RAS, renin angiotensin system; RAAS, renin angiotensin aldosterone system; ROS/RNS, reactive oxygen species/reactive nitrogen species. UV, ultraviolet; VE-CAM, vascular endothelial cellular adhesion molecule.
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Figure 17. Vicious cycles and multiple injurious hits combine to result in small vessel disease (SVD), neuronal injury, neurodegeneration, brain atrophy, impaired cognition, and LOAD. Panel (A) depicts the importance of the vicious cycle between oxidative-redox stress (OxRS) and inflammation resulting in microvessel remodeling and cerebral small vessel disease (SVD), which contribute to impaired cognition and the development of neurodegeneration. Panel (B) depicts the multiple injurious hits that trigger the OxRS and neuroinflammation, which are involved in the development of neuronal injury and neurodegeneration. Panel (A) is reproduced with permission by 4.0 [36]. Act, activation; BBB, blood–brain barrier; BBBdd, blood–brain barrier dysfunction and disruption; BEC, brain endothelial cell; CMBs, cerebral microbleeds; cnsCC, central nervous system cytokines/chemokines; dys, dysfunction; EPVS, enlarged perivascular spaces; MMP, matrix metalloproteinases; NFkappaB, nuclear factor kappa beta; pCC, peripheral cytokines/chemokines; ROS, reactive oxygen species; RONSS, reactive oxygen, nitrogen, sulfur species; RSI, reactive species interactome; TJ/AJ, tight and adherens junctions; VE, vascular endothelial.
Figure 17. Vicious cycles and multiple injurious hits combine to result in small vessel disease (SVD), neuronal injury, neurodegeneration, brain atrophy, impaired cognition, and LOAD. Panel (A) depicts the importance of the vicious cycle between oxidative-redox stress (OxRS) and inflammation resulting in microvessel remodeling and cerebral small vessel disease (SVD), which contribute to impaired cognition and the development of neurodegeneration. Panel (B) depicts the multiple injurious hits that trigger the OxRS and neuroinflammation, which are involved in the development of neuronal injury and neurodegeneration. Panel (A) is reproduced with permission by 4.0 [36]. Act, activation; BBB, blood–brain barrier; BBBdd, blood–brain barrier dysfunction and disruption; BEC, brain endothelial cell; CMBs, cerebral microbleeds; cnsCC, central nervous system cytokines/chemokines; dys, dysfunction; EPVS, enlarged perivascular spaces; MMP, matrix metalloproteinases; NFkappaB, nuclear factor kappa beta; pCC, peripheral cytokines/chemokines; ROS, reactive oxygen species; RONSS, reactive oxygen, nitrogen, sulfur species; RSI, reactive species interactome; TJ/AJ, tight and adherens junctions; VE, vascular endothelial.
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Figure 18. Neuroinflammation induces neurodegeneration via proinflammatory central nervous system cytokines and chemokines (cnsCC), amyloid beta (Aβ), and tau. (A) reveals a cleaned transmission electron microscopy (TEM) image of a reactive microglia (rMGC). (B) depicts an illustration of a reactive astrocyte (rAC). (C) represents an illustration of a myelinated neuron. (D) depicts a portion of a myelinated neuronal axon that importantly depicts aberrant mitochondria (aMt) capable of leaking mitochondria reactive oxygen species (mtROS) and splitting of myelin that could impair informational transfer. (E) depicts a TEM image of a dendritic neurite (dn) outlined with yellow-dashed lines. (F,G) depict a TEM image of an Aβ plaque outlined by yellow-dashed lines. (H,I) depict immunohistologic light microscope images of Aβ. Image G scale bar = 5 μm. (I) scale bar = 20 μm. Modified (A,D) provided with permission by CC 4.0 [60,61]. (H,I) provided with permission by CC 4.0 [74]. aMt, aberrant mitochondria; CC, chromatin condensation; COX, cyclooxygenase; cnsCC, central nervous system cytokines chemokines; dn, dendritic neurite; IL-1, interleukin 1; IL-1β, interleukin 1 beta; IL-6, interleukin 6; ISC, iron sulfur clusters; Lys, lysosome; mtROS, mitochondria reactive oxygen species; N, nucleus; NADPH Ox, nicotine adenine diphosphate oxidase; NFTs, neuro fibrillary tangles; NO, nitric oxide; NOX, NADPH Ox; OxRS, oxidative redox stress; rACs, reactive astrocytes; rMGCs, reactive microglia cells; TNFα, tumor necrosis alpha.
Figure 18. Neuroinflammation induces neurodegeneration via proinflammatory central nervous system cytokines and chemokines (cnsCC), amyloid beta (Aβ), and tau. (A) reveals a cleaned transmission electron microscopy (TEM) image of a reactive microglia (rMGC). (B) depicts an illustration of a reactive astrocyte (rAC). (C) represents an illustration of a myelinated neuron. (D) depicts a portion of a myelinated neuronal axon that importantly depicts aberrant mitochondria (aMt) capable of leaking mitochondria reactive oxygen species (mtROS) and splitting of myelin that could impair informational transfer. (E) depicts a TEM image of a dendritic neurite (dn) outlined with yellow-dashed lines. (F,G) depict a TEM image of an Aβ plaque outlined by yellow-dashed lines. (H,I) depict immunohistologic light microscope images of Aβ. Image G scale bar = 5 μm. (I) scale bar = 20 μm. Modified (A,D) provided with permission by CC 4.0 [60,61]. (H,I) provided with permission by CC 4.0 [74]. aMt, aberrant mitochondria; CC, chromatin condensation; COX, cyclooxygenase; cnsCC, central nervous system cytokines chemokines; dn, dendritic neurite; IL-1, interleukin 1; IL-1β, interleukin 1 beta; IL-6, interleukin 6; ISC, iron sulfur clusters; Lys, lysosome; mtROS, mitochondria reactive oxygen species; N, nucleus; NADPH Ox, nicotine adenine diphosphate oxidase; NFTs, neuro fibrillary tangles; NO, nitric oxide; NOX, NADPH Ox; OxRS, oxidative redox stress; rACs, reactive astrocytes; rMGCs, reactive microglia cells; TNFα, tumor necrosis alpha.
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Figure 19. Microvessel SVD definitely contributes to and are linked to the development of neurodegeneration. At least a half dozen mechanisms are involved. Importantly, note that number 5 points to the quartet of mechanisms involved in this linkage of SVD to neurodegeneration. Importantly these six mechanisms of linage seem to be initiated by brain endothelial cell activation and dysfunction (BECact/dys) with concurrent blood–brain barrier dysfunction and/or disruption (BBBdd). Aβ, amyloid beta; CBF, cerebral blood flow; EPVS, enlarged perivascular spaces, LOAD, late-onset Alzheimer’s disease; SVD, small vessel disease.
Figure 19. Microvessel SVD definitely contributes to and are linked to the development of neurodegeneration. At least a half dozen mechanisms are involved. Importantly, note that number 5 points to the quartet of mechanisms involved in this linkage of SVD to neurodegeneration. Importantly these six mechanisms of linage seem to be initiated by brain endothelial cell activation and dysfunction (BECact/dys) with concurrent blood–brain barrier dysfunction and/or disruption (BBBdd). Aβ, amyloid beta; CBF, cerebral blood flow; EPVS, enlarged perivascular spaces, LOAD, late-onset Alzheimer’s disease; SVD, small vessel disease.
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Figure 20. Gross brain atrophy in the db/db obese diabetic model but not in the obese diabetic BTBR ob/ob model or obese and diabetic db/db models treated with empagliflozin. Panel (A) demonstrates the normal gross brain in the control male model at 20-weeks of age. Panel (B) depicts marked brain atrophy at the time of surgical removal of the diabetic db/db models as compared to control models in Panel (A). Note the marked atrophy or loss in the cortical-parietal-hippocampal regions (outlined by the yellow dashed lines) in panel (B) as compared to the control in panel (A) at 26-weeks of age and these remodeling changes were associated with a decrease in the brain wet weights upon removal. Panel (C) demonstrates the absence of remodeling atrophy in the ob/ob diabetic obese model at 20-weeks of age and also those db/db diabetic models treated with empagliflozin at 26-weeks of age. Modified panels (A,B) were provided with permission by CC 4.0 [114,115].
Figure 20. Gross brain atrophy in the db/db obese diabetic model but not in the obese diabetic BTBR ob/ob model or obese and diabetic db/db models treated with empagliflozin. Panel (A) demonstrates the normal gross brain in the control male model at 20-weeks of age. Panel (B) depicts marked brain atrophy at the time of surgical removal of the diabetic db/db models as compared to control models in Panel (A). Note the marked atrophy or loss in the cortical-parietal-hippocampal regions (outlined by the yellow dashed lines) in panel (B) as compared to the control in panel (A) at 26-weeks of age and these remodeling changes were associated with a decrease in the brain wet weights upon removal. Panel (C) demonstrates the absence of remodeling atrophy in the ob/ob diabetic obese model at 20-weeks of age and also those db/db diabetic models treated with empagliflozin at 26-weeks of age. Modified panels (A,B) were provided with permission by CC 4.0 [114,115].
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Figure 21. Vascular contributions to cognitive impairment and dementia (VCID) are central to the development of neurodegeneration and late-onset Alzheimer’s disease (LOAD) and/or mixed dementia (MD). Cardio-cerebrovascular diseases including stroke (ischemic and hemorrhagic) associate with and contribute to brain endothelial cell activation and dysfunction (BECact/dys) with concurrent blood–brain barrier dysfunction and disruption (BBBdd) induced ischemia, hypoxia, and chronic cerebral hypoperfusion (CCH) to result in neurodegeneration and dementia in LOAD and MD.
Figure 21. Vascular contributions to cognitive impairment and dementia (VCID) are central to the development of neurodegeneration and late-onset Alzheimer’s disease (LOAD) and/or mixed dementia (MD). Cardio-cerebrovascular diseases including stroke (ischemic and hemorrhagic) associate with and contribute to brain endothelial cell activation and dysfunction (BECact/dys) with concurrent blood–brain barrier dysfunction and disruption (BBBdd) induced ischemia, hypoxia, and chronic cerebral hypoperfusion (CCH) to result in neurodegeneration and dementia in LOAD and MD.
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Figure 22. The dementia quartet mechanisms intersect and contribute to neurodegeneration with neuronal synapse and neuron dysfunction and or loss with regional brain atrophy in late-onset Alzheimer’s disease (LOAD) and mixed dementia (MD) in addition to the small vessel disease (SVD) intersection and contribution to neurodegeneration, LOAD, and MD.
Figure 22. The dementia quartet mechanisms intersect and contribute to neurodegeneration with neuronal synapse and neuron dysfunction and or loss with regional brain atrophy in late-onset Alzheimer’s disease (LOAD) and mixed dementia (MD) in addition to the small vessel disease (SVD) intersection and contribution to neurodegeneration, LOAD, and MD.
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Figure 23. Future directions in microvessel small vessel disease that contribute to late-onset Alzheimer’s disease. BECact/dys, brain endothelial cell activation and dysfunction; BBBdd, blood–brain barrier dysfunction and disruption; BH4, tetrahydrobiopterin; cnsCC, central nervous system cytokines chemokines; eNOS, endothelial nitric oxide synthase; H2S, hydrogen sulfide; LOAD, late-onset Alzheimer’s disease; MMP, matrix metalloproteinase; NO, nitric oxide; OxRS, oxidative redox stress; pCC, peripheral cytokines chemokines; SVD, small vessel disease; T, tesla; tPA, tissue-type plasminogen activator; VaD/VAD, vascular dementia.
Figure 23. Future directions in microvessel small vessel disease that contribute to late-onset Alzheimer’s disease. BECact/dys, brain endothelial cell activation and dysfunction; BBBdd, blood–brain barrier dysfunction and disruption; BH4, tetrahydrobiopterin; cnsCC, central nervous system cytokines chemokines; eNOS, endothelial nitric oxide synthase; H2S, hydrogen sulfide; LOAD, late-onset Alzheimer’s disease; MMP, matrix metalloproteinase; NO, nitric oxide; OxRS, oxidative redox stress; pCC, peripheral cytokines chemokines; SVD, small vessel disease; T, tesla; tPA, tissue-type plasminogen activator; VaD/VAD, vascular dementia.
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MDPI and ACS Style

Hayden, M.R. Paying Homage to Microvessel Remodeling and Small Vessel Disease in Neurodegeneration: Implications for the Development of Late-Onset Alzheimer’s Disease. J. Vasc. Dis. 2024, 3, 419-452. https://doi.org/10.3390/jvd3040033

AMA Style

Hayden MR. Paying Homage to Microvessel Remodeling and Small Vessel Disease in Neurodegeneration: Implications for the Development of Late-Onset Alzheimer’s Disease. Journal of Vascular Diseases. 2024; 3(4):419-452. https://doi.org/10.3390/jvd3040033

Chicago/Turabian Style

Hayden, Melvin R. 2024. "Paying Homage to Microvessel Remodeling and Small Vessel Disease in Neurodegeneration: Implications for the Development of Late-Onset Alzheimer’s Disease" Journal of Vascular Diseases 3, no. 4: 419-452. https://doi.org/10.3390/jvd3040033

APA Style

Hayden, M. R. (2024). Paying Homage to Microvessel Remodeling and Small Vessel Disease in Neurodegeneration: Implications for the Development of Late-Onset Alzheimer’s Disease. Journal of Vascular Diseases, 3(4), 419-452. https://doi.org/10.3390/jvd3040033

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