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Infections, Inflammation and Neurodegeneration in Alzheimer's Disease

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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 (1 December 2021) | Viewed by 42232

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Dr. Federico Licastro

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Department of Experimental, Diagnostic, Specialty Medicine School of Medicine University of Bologna, Bologna, Italy
Interests: genetic and environmental AD risk factors; brain immune mechanisms; virus infections; AD prevention; predictive medicine; AD risk; chart; personalized AD risk assessment
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Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. With the rapid advancement of gene typing technologies and genome-wide association studies, several AD risk genes have so far been identified and confirmed, including CLU, CR1, PICALM, SORL1, TREM2, and CD33. However, apart from APOE polymorphism, each gene has a limited OR for AD. It is of interest that all these genes are involved in different immune responses against pathogens.

Microbes are emerging risk factors for the disease and substantial new data have been recently published supporting the general hypothesis that virus, some bacteria, and fungi appear to be associated with the clinical history of dementia. Moreover, infections may also be involved in brain inflammation and some aspects of neurodegeneration associated with AD.

In this Special Issue of the International Journal of Molecular Sciences, the main topic will be infections, inflammation and neuro-degeneration in Alzheimer's disease. It is dedicated to research articles and reviews regarding infectious agents associated with AD, immune mechanisms involved in the brain defenses, inflammatory processes, and neuro-pathological markers of AD. The emphasis will be on novel AD-related mechanism of infections, brain reaction to these invaders and the brain and systemic inflammatory responses against brain AD-related pathogens and their involvement in neurodegenerative mechanisms. New insights for infection diagnosis, identification of potential pathogenic pathways, therapeutic and preventive measures and vaccination are the focus of this Special Issue of the International Journal of Molecular Sciences.

Dr. Federico Licastro
Guest Editor

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Keywords

virus, bacterial and fungal infections
AD pathogenesis and CNS and peripheral inflammation
amyloid peptides
brain amyloid and anti-microorganism defense
gene signature and brain infections
APOE gene and infections
dementia and anti-infective therapy
vaccination and AD
risk factors and dementia prevention.

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Published Papers (9 papers)

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Editorial

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6 pages, 308 KiB

Open AccessEditorial

Special Issue Editorial: “Infections, Inflammation and Neurodegeneration in Alzheimer Disease” Infections, Neuronal Senescence, and Dementia

by Federico Licastro

Int. J. Mol. Sci. 2022, 23(11), 5865; https://doi.org/10.3390/ijms23115865 - 24 May 2022

Cited by 3 | Viewed by 1991

Abstract

Alzheimer’s disease (AD) is a complex chronic disease of the brain characterized by several neurodegenerative mechanisms and is responsible for most dementia cases in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation, and chronic neuroinflammation is a constant component of AD brain pathology. In the Special Issue published in 2021 eight papers were collected regarding different aspects of neurodegeneration associated with AD. Five papers presented and discussed infectious agents involved in brain AD pathology and three discussed data regarding receptors regulation and possible treatment of the disease. Below I will discuss and further elaborate on topics related to infections, inflammation, and neurodegenerative pathways in AD and brain senescence. The topic presented here may contribute to early intervention protocols for preventing or slowing the progression of cognitive deterioration in the elderly. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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Research

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13 pages, 2079 KiB

Open AccessArticle

SARS-CoV-2 Exacerbates Beta-Amyloid Neurotoxicity, Inflammation and Oxidative Stress in Alzheimer’s Disease Patients

by Luigi Chiricosta, Agnese Gugliandolo and Emanuela Mazzon

Int. J. Mol. Sci. 2021, 22(24), 13603; https://doi.org/10.3390/ijms222413603 - 19 Dec 2021

Cited by 39 | Viewed by 4041

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the pandemic Coronavirus Disease 19 (COVID-19), causing millions of deaths. The elderly and those already living with comorbidity are likely to die after SARS-CoV-2 infection. People suffering from Alzheimer’s disease (AD) have a higher risk of becoming infected, because they cannot easily follow health roles. Additionally, those suffering from dementia have a 40% higher risk of dying from COVID-19. Herein, we collected from Gene Expression Omnibus repository the brain samples of AD patients who died of COVID-19 (AD+COVID-19), AD without COVID-19 (AD), COVID-19 without AD (COVID-19) and control individuals. We inspected the transcriptomic and interactomic profiles by comparing the COVID-19 cohort against the control cohort and the AD cohort against the AD+COVID-19 cohort. SARS-CoV-2 in patients without AD mainly activated processes related to immune response and cell cycle. Conversely, 21 key nodes in the interactome are deregulated in AD. Interestingly, some of them are linked to beta-amyloid production and clearance. Thus, we inspected their role, along with their interactors, using the gene ontologies of the biological process that reveals their contribution in brain organization, immune response, oxidative stress and viral replication. We conclude that SARS-CoV-2 worsens the AD condition by increasing neurotoxicity, due to higher levels of beta-amyloid, inflammation and oxidative stress. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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17 pages, 4040 KiB

Open AccessArticle

Oral Pathogenic Bacteria-Inducing Neurodegenerative Microgliosis in Human Neural Cell Platform

by Van Thi Ai Tran, You Jung Kang, Hyun-Kyoung Kim, Hyung-Ryong Kim and Hansang Cho

Int. J. Mol. Sci. 2021, 22(13), 6925; https://doi.org/10.3390/ijms22136925 - 28 Jun 2021

Cited by 15 | Viewed by 4150

Abstract

Porphyromonas gingivalis is a gram-negative bacterium found in the human oral cavity and is responsible for the development of chronic periodontitis as well as neurological diseases, including Alzheimer’s disease (AD). Given the significance of the roles of P. gingivalis in AD pathogenesis, it is critical to understand the underlying mechanisms of P. gingivalis-driven neuroinflammation and their contribution to neurodegeneration. Herein, we hypothesize that P. gingivalis produces secondary metabolites that may cause neurodegeneration through direct or indirect pathways mediated by microglia. To test our hypothesis, we treated human neural cells with bacterial conditioned media on our brain platforms and assessed microgliosis, astrogliosis and neurodegeneration. We found that bacteria-mediated microgliosis induced the production of nitric oxide, which causes neurodegeneration assessed with high pTau level. Our study demonstrated the elevation of detrimental protein mediators, CD86 and iNOS and the production of several pro-inflammatory markers from stimulated microglia. Through inhibition of LPS and succinate dehydrogenase in a bacterial conditioned medium, we showed a decrease in neurodegenerative microgliosis. In addition, we demonstrated the bidirectional effect of microgliosis and astrogliosis on each other exacerbating neurodegeneration. Overall, our study suggests that the mouth-brain axis may contribute to the pathogenesis of AD. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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Graphical abstract

20 pages, 5250 KiB

Open AccessArticle

Meta-Analysis of Methamphetamine Modulation on Amyloid Precursor Protein through HMGB1 in Alzheimer’s Disease

by Sedra Alabed, Heping Zhou, Ilker K. Sariyer and Sulie L. Chang

Int. J. Mol. Sci. 2021, 22(9), 4781; https://doi.org/10.3390/ijms22094781 - 30 Apr 2021

Cited by 16 | Viewed by 3473

Abstract

The deposition of amyloid-beta (Aβ) through the cleavage of amyloid-beta precursor protein (APP) is a biomarker of Alzheimer’s disease (AD). This study used QIAGEN Ingenuity Pathway Analysis (IPA) to conduct meta-analysis on the molecular mechanisms by which methamphetamine (METH) impacts AD through modulating the expression of APP. All the molecules affected by METH and APP were collected from the QIAGEN Knowledge Base (QKB); 78 overlapping molecules were identified. Upon simulation of METH exposure using the “Molecule Activity Predictor” feature, eight molecules were found to be affected by METH and exhibited activation relationships on APP expression at a confidence of p = 0.000453 (Z-score = 3.51, two-tailed). Core Analysis of these eight molecules identified High Mobility Group Box protein 1 (HMGB1) signaling pathway among the top 5 canonical pathways with most overlap with the 8-molecule dataset. Simulated METH exposure increased APP expression through HMGB1 at a confidence of p < 0.00001 (Z-score = 7.64, two-tailed). HMGB1 is a pathogenic hallmark in AD progression. It not only increases the production of inflammatory mediators, but also mediates the disruption of the blood-brain barrier. Our analyses suggest the involvement of HMGB1 signaling pathway in METH-induced modulation of APP as a potential casual factor of AD. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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Review

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32 pages, 8723 KiB

Open AccessReview

Disrupting Neurons and Glial Cells Oneness in the Brain—The Possible Causal Role of Herpes Simplex Virus Type 1 (HSV-1) in Alzheimer’s Disease

by Matylda Barbara Mielcarska, Katarzyna Skowrońska, Zbigniew Wyżewski and Felix Ngosa Toka

Int. J. Mol. Sci. 2022, 23(1), 242; https://doi.org/10.3390/ijms23010242 - 27 Dec 2021

Cited by 12 | Viewed by 6213

Abstract

Current data strongly suggest herpes simplex virus type 1 (HSV-1) infection in the brain as a contributing factor to Alzheimer’s disease (AD). The consequences of HSV-1 brain infection are multilateral, not only are neurons and glial cells damaged, but modifications also occur in their environment, preventing the transmission of signals and fulfillment of homeostatic and immune functions, which can greatly contribute to the development of disease. In this review, we discuss the pathological alterations in the central nervous system (CNS) cells that occur, following HSV-1 infection. We describe the changes in neurons, astrocytes, microglia, and oligodendrocytes related to the production of inflammatory factors, transition of glial cells into a reactive state, oxidative damage, Aβ secretion, tau hyperphosphorylation, apoptosis, and autophagy. Further, HSV-1 infection can affect processes observed during brain aging, and advanced age favors HSV-1 reactivation as well as the entry of the virus into the brain. The host activates pattern recognition receptors (PRRs) for an effective antiviral response during HSV-1 brain infection, which primarily engages type I interferons (IFNs). Future studies regarding the influence of innate immune deficits on AD development, as well as supporting the neuroprotective properties of glial cells, would reveal valuable information on how to harness cytotoxic inflammatory milieu to counter AD initiation and progression. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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36 pages, 4534 KiB

Open AccessReview

Role of Receptors in Relation to Plaques and Tangles in Alzheimer’s Disease Pathology

by Kavita Sharma, Samjhana Pradhan, Lawrence K. Duffy, Sabina Yeasmin, Nirajan Bhattarai and Marvin K. Schulte

Int. J. Mol. Sci. 2021, 22(23), 12987; https://doi.org/10.3390/ijms222312987 - 30 Nov 2021

Cited by 25 | Viewed by 5264

Abstract

Despite the identification of Aβ plaques and NFTs as biomarkers for Alzheimer’s disease (AD) pathology, therapeutic interventions remain elusive, with neither an absolute prophylactic nor a curative medication available to impede the progression of AD presently available. Current approaches focus on symptomatic treatments to maintain AD patients’ mental stability and behavioral symptoms by decreasing neuronal degeneration; however, the complexity of AD pathology requires a wide range of therapeutic approaches for both preventive and curative treatments. In this regard, this review summarizes the role of receptors as a potential target for treating AD and focuses on the path of major receptors which are responsible for AD progression. This review gives an overall idea centering on major receptors, their agonist and antagonist and future prospects of viral mimicry in AD pathology. This article aims to provide researchers and developers a comprehensive idea about the different receptors involved in AD pathogenesis that may lead to finding a new therapeutic strategy to treat AD. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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14 pages, 2656 KiB

Open AccessReview

Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer’s Disease

by Federico Licastro and Elisa Porcellini

Int. J. Mol. Sci. 2021, 22(14), 7263; https://doi.org/10.3390/ijms22147263 - 6 Jul 2021

Cited by 16 | Viewed by 3710

Abstract

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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14 pages, 1790 KiB

Open AccessReview

Homocysteine and Age-Related Central Nervous System Diseases: Role of Inflammation

by Amany Tawfik, Nehal M. Elsherbiny, Yusra Zaidi and Pragya Rajpurohit

Int. J. Mol. Sci. 2021, 22(12), 6259; https://doi.org/10.3390/ijms22126259 - 10 Jun 2021

Cited by 24 | Viewed by 8591

Abstract

Hyperhomocysteinemia (HHcy) is remarkably common among the aging population. The relation between HHcy and the development of neurodegenerative diseases, such as Alzheimer’s disease (AD) and eye diseases, and age-related macular degeneration (AMD) and diabetic retinopathy (DR) in elderly people, has been established. Disruption of the blood barrier function of the brain and retina is one of the most important underlying mechanisms associated with HHcy-induced neurodegenerative and retinal disorders. Impairment of the barrier function triggers inflammatory events that worsen disease pathology. Studies have shown that AD patients also suffer from visual impairments. As an extension of the central nervous system, the retina has been suggested as a prominent site of AD pathology. This review highlights inflammation as a possible underlying mechanism of HHcy-induced barrier dysfunction and neurovascular injury in aging diseases accompanied by HHcy, focusing on AD. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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16 pages, 12162 KiB

Open AccessReview

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

by Klaus Grossmann

Int. J. Mol. Sci. 2021, 22(9), 4805; https://doi.org/10.3390/ijms22094805 - 30 Apr 2021

Cited by 14 | Viewed by 3681

Abstract

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment. Full article

(This article belongs to the Special Issue Infections, Inflammation and Neurodegeneration in Alzheimer's Disease)

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