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Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 17299

Special Issue Editor

Prof. Dr. Masashi Tanaka

E-Mail Website
Guest Editor
Department of Physical Therapy, Health Science University, 7187 Kodachi, Fujikawaguchiko-machi, Minamitsuru-gun, Yamanashi 401-0380, Japan
Interests: amyloid-beta; dementia; type 2 diabetes; innate immune system; inflammation; microglia; obesity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The incidence of dementia continues to expand worldwide; however, there are currently no effective therapeutic strategies for this disabling neurocognitive disorder. Therefore, there is an urgent need to elucidate the underlying mechanisms and develop novel therapeutics for the effective treatment of dementia.

Alzheimer’s disease (AD) is one of the main causes of dementia, induced by amyloid-β accumulation and subsequent tau hyperphosphorylation in the brain, which results in neuronal injury and cognitive impairment. Furthermore, cerebrovascular amyloid-β deposition can cause vascular cognitive impairment (VCI). Various mechanisms are involved in eliminating amyloid-β from the brain, and one of them is microglial phagocytosis. Accumulating evidence has further proven the role of microglia in the pathogenesis of these diseases. Amyloid-β accumulation and tau aggregates induce microglial activation, thereby triggering inflammatory responses. Moreover, metabolic diseases such as type 2 diabetes and obesity, as well as aging, affect microglial function deleteriously and trigger neuroinflammation. As neuroinflammation is implicated in exacerbating dementia-related brain pathologies, these findings highlight the need to suppress neuroinflammation to prevent cognitive impairment.

This Special Issue is intended to provide novel insights into the underlying mechanisms, potential targets and/or new agents for suppressing neuroinflammation, thereby contributing to the development of innovative strategies for preventing and improving AD and related dementias. We welcome original articles and reviews related to this research topic.

Prof. Dr. Masashi Tanaka
Guest Editor

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Keywords

  • Alzheimer’s disease
  • amyloid-β
  • cerebrovascular diseases
  • metabolic diseases
  • microglia
  • neurocognitive disorders
  • neuroinflammation
  • tau
  • type 2 diabetes
  • vascular cognitive impairment

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Published Papers (6 papers)

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Research

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14 pages, 2396 KiB  
Article
The Phytochemical Agathisflavone Modulates miR146a and miR155 in Activated Microglia Involving STAT3 Signaling
by Balbino Lino dos Santos, Cleonice Creusa dos Santos, Karina Costa da Silva, Carolina Kymie Vasques Nonaka, Bruno Solano de Freitas Souza, Jorge Mauricio David, Juciele Valéria Ribeiro de Oliveira, Maria de Fátima Dias Costa, Arthur Morgan Butt, Victor Diogenes Amaral da Silva and Silvia Lima Costa
Int. J. Mol. Sci. 2024, 25(5), 2547; https://doi.org/10.3390/ijms25052547 - 22 Feb 2024
Cited by 3 | Viewed by 1441
Abstract
MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves [...] Read more.
MicroRNAs (miRs) act as important post-transcriptional regulators of gene expression in glial cells and have been shown to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Here, we investigated the effects of agathisflavone, a biflavonoid purified from the leaves of Cenostigma pyramidale (Tul.), on modulating the expression of miRs and inflammatory mediators in activated microglia. C20 human microglia were exposed to oligomers of the β-amyloid peptide (Aβ, 500 nM) for 4 h or to lipopolysaccharide (LPS, 1 µg/mL) for 24 h and then treated or not with agathisflavone (1 µM) for 24 h. We observed that β-amyloid and LPS activated microglia to an inflammatory state, with increased expression of miR-146a, miR-155, IL1-β, IL-6, and NOS2. Treatment with agathisflavone resulted in a significant reduction in miR146a and miR-155 induced by LPS or Aβ, as well as inflammatory cytokines IL1-β, IL-6, and NOS2. In cells stimulated with Aβ, there was an increase in p-STAT3 expression that was reduced by agathisflavone treatment. These data identify a role for miRs in the anti-inflammatory effect of agathisflavone on microglia in models of neuroinflammation and AD. Full article
(This article belongs to the Special Issue Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)
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17 pages, 3574 KiB  
Article
The Role of Intracellular Ca2+ and Mitochondrial ROS in Small Aβ1-42 Oligomer-Induced Microglial Death
by Aiste Jekabsone, Silvija Jankeviciute, Katryna Pampuscenko, Vilmante Borutaite and Ramune Morkuniene
Int. J. Mol. Sci. 2023, 24(15), 12315; https://doi.org/10.3390/ijms241512315 - 1 Aug 2023
Cited by 7 | Viewed by 1639
Abstract
Alzheimer’s disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ1-42 structure and toxicity is of major interest. NMDA receptors [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ1-42 structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ1-42 species—small oligomers, large oligomers, insoluble fibrils, and monomers—were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ1-42 oligomers induced a concentration- and time-dependent increase in intracellular Ca2+ and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca2+ nor viability was significantly affected by larger Aβ1-42 species or monomers. In addition, the small Aβ1-42 oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ1-42-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy. Full article
(This article belongs to the Special Issue Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)
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17 pages, 3319 KiB  
Article
Opioids Alleviate Oxidative Stress via the Nrf2/HO-1 Pathway in LPS-Stimulated Microglia
by Akash Shivling Mali, Ondrej Honc, Lucie Hejnova and Jiri Novotny
Int. J. Mol. Sci. 2023, 24(13), 11089; https://doi.org/10.3390/ijms241311089 - 4 Jul 2023
Cited by 5 | Viewed by 2299
Abstract
Opioids are known to have antioxidant effects and to modulate microglial function under certain conditions. It has been previously shown that opioid ligands can effectively inhibit the release of proinflammatory cytokines when stimulated with lipopolysaccharide (LPS) and convert microglia to an anti-inflammatory polarization [...] Read more.
Opioids are known to have antioxidant effects and to modulate microglial function under certain conditions. It has been previously shown that opioid ligands can effectively inhibit the release of proinflammatory cytokines when stimulated with lipopolysaccharide (LPS) and convert microglia to an anti-inflammatory polarization state. Here, we used C8-B4 cells, the mouse microglial cell line activated by LPS as a model to investigate the anti-inflammatory/antioxidant potential of selected opioid receptor agonists (DAMGO, DADLE, and U-50488). We found that all of these ligands could exert cytoprotective effects through the mechanism affecting LPS-induced ROS production, NADPH synthesis, and glucose uptake. Interestingly, opioids elevated the level of reduced glutathione, increased ATP content, and enhanced mitochondrial respiration in microglial cells exposed to LPS. These beneficial effects were associated with the upregulation of the Nrf2/HO-1 pathway. The present results indicate that activation of opioid signaling supports the preservation of mitochondrial function with concomitant elimination of ROS in microglia and suggest that an Nrf2/HO-1 signaling pathway-dependent mechanism is involved in the antioxidant efficacy of opioids. Opioid receptor agonists may therefore be considered as agents to suppress oxidative stress and inflammatory responses of microglia. Full article
(This article belongs to the Special Issue Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)
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15 pages, 1227 KiB  
Article
TREM2 Expression and Amyloid-Beta Phagocytosis in Alzheimer’s Disease
by Francesca La Rosa, Simone Agostini, Federica Piancone, Ivana Marventano, Ambra Hernis, Chiara Fenoglio, Daniela Galimberti, Elio Scarpini, Marina Saresella and Mario Clerici
Int. J. Mol. Sci. 2023, 24(10), 8626; https://doi.org/10.3390/ijms24108626 - 11 May 2023
Cited by 12 | Viewed by 3010
Abstract
Alzheimer’s Disease is the most common form of dementia; its key pathological findings include the deposition of extracellular-neurotoxic-plaques composed of amyloid-beta (Ab). AD-pathogenesis involves mechanisms that operate outside the brain, and new researches indicate that peripheral inflammation is an early event in the [...] Read more.
Alzheimer’s Disease is the most common form of dementia; its key pathological findings include the deposition of extracellular-neurotoxic-plaques composed of amyloid-beta (Ab). AD-pathogenesis involves mechanisms that operate outside the brain, and new researches indicate that peripheral inflammation is an early event in the disease. Herein, we focus on a receptor known as triggering-receptor-expressed-on-myeloid-cells2 (TREM2), which promotes the optimal immune cells function required to attenuate AD-progression and is, therefore, a potential target as peripheral diagnostic and prognostic-biomarker for Alzheimer’s Disease. The objective of this exploratory study was to analyze: (1) soluble-TREM2 (sTREM2) plasma and cerebrospinal fluid concentration, (2) TREM2-mRNA, (3) the percentage of TREM2-expressing monocytes, and (4) the concentration of miR-146a-5p and miR-34a-5p suspected to influence TREM2 transcription. Experiments were performed on PBMC collected by 15AD patients and 12age-matched healthy controls that were unstimulated or treated in inflammatory (LPS) conditions and Ab42 for 24 h; Aβ42-phagocytosis was also analyzed by AMNIS FlowSight. Results although preliminary, due to limitations by the small sample-size, showed that in AD compared to HC: TREM2 expressing monocytes were reduced, plasma sTREM2 concentration and TREM2-mRNA were significantly upregulated and Ab42-phagocytosis was diminished (for all p < 0.05). miR-34a-5p expression was reduced (p = 0.02) as well in PBMC of AD, and miR-146 was only observed in AD cells (p = 0.0001). Full article
(This article belongs to the Special Issue Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)
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Review

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15 pages, 761 KiB  
Review
A State-of-Art Review of the Vicious Circle of Sleep Disorders, Diabetes and Neurodegeneration Involving Metabolism and Microbiota Alterations
by Salvatore Versace, Gaia Pellitteri, Roberto Sperotto, Sara Tartaglia, Andrea Da Porto, Cristiana Catena, Gian Luigi Gigli, Alessandro Cavarape and Mariarosaria Valente
Int. J. Mol. Sci. 2023, 24(13), 10615; https://doi.org/10.3390/ijms241310615 - 25 Jun 2023
Cited by 7 | Viewed by 2917
Abstract
In the context of neurodegenerative disorders, cognitive decline is frequently reported in older population. Recently, numerous metabolic pathways have been implicated in neurodegeneration, including signaling disruption of insulin and other glucose-regulating hormones. In fact, Alzheimer’s disease has now been considered as “type-3 diabetes”. [...] Read more.
In the context of neurodegenerative disorders, cognitive decline is frequently reported in older population. Recently, numerous metabolic pathways have been implicated in neurodegeneration, including signaling disruption of insulin and other glucose-regulating hormones. In fact, Alzheimer’s disease has now been considered as “type-3 diabetes”. In this review, we tried to clarify the role of sleep impairment as the third major player in the complex relationship between metabolic and neurodegenerative diseases. Altered sleep may trigger or perpetuate these vicious mechanisms, leading to the development of both dementia and type 2 diabetes mellitus. Finally, we analyzed these reciprocal interactions considering the emerging role of the gut microbiota in modulating the same processes. Conditions of dysbiosis have been linked to circadian rhythm disruption, metabolic alterations, and release of neurotoxic products, all contributing to neurodegeneration. In a future prospective, gut microbiota could provide a major contribution in explaining the tangled relationship between sleep disorders, dementia and diabetes. Full article
(This article belongs to the Special Issue Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)
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53 pages, 12133 KiB  
Review
Tacrine-Based Hybrids: Past, Present, and Future
by Anna Bubley, Alexaner Erofeev, Peter Gorelkin, Elena Beloglazkina, Alexander Majouga and Olga Krasnovskaya
Int. J. Mol. Sci. 2023, 24(2), 1717; https://doi.org/10.3390/ijms24021717 - 15 Jan 2023
Cited by 13 | Viewed by 4844
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder which is characterized by β-amyloid (Aβ) aggregation, τ-hyperphosphorylation, and loss of cholinergic neurons. The other important hallmarks of AD are oxidative stress, metal dyshomeostasis, inflammation, and cell cycle dysregulation. Multiple therapeutic targets may be proposed for the development of anti-AD drugs, and the “one drug–multiple targets” strategy is of current interest. Tacrine (THA) was the first clinically approved cholinesterase (ChE) inhibitor, which was withdrawn due to high hepatotoxicity. However, its high potency in ChE inhibition, low molecular weight, and simple structure make THA a promising scaffold for developing multi-target agents. In this review, we summarized THA-based hybrids published from 2006 to 2022, thus providing an overview of strategies that have been used in drug design and approaches that have resulted in significant cognitive improvements and reduced hepatotoxicity. Full article
(This article belongs to the Special Issue Novel Research of Neuroinflammation in the Pathogenesis of Alzheimer's Disease and Related Dementias)
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