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Neuroinflammation in the Pathogenesis of Alzheimer’s Disease and Related Dementias: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 20 September 2025 | Viewed by 1414

Special Issue Editor

Prof. Dr. Amal Kaddoumi

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912, United States
Interests: Alzheimer's disease; cerebral amyloid angiopathy; blood-brain barrier; neuroinflammation; amyloid-β
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issue on “Neuroinflammation in the Pathogenesis of Alzheimer’s Disease and Related Dementias”.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. In addition to memory loss and progressive dementia, AD is characterized by several pathological hallmarks including the deposition of amyloid-β(Aβ) plaques, neurofibrillary tangles (NFT) of hyper-phosphorylated tau, blood–brain barrier breakdown, oxidative stress, and neuronal loss. In addition, neuroinflammation has a prominent role in the pathogenesis of AD, as suggested by the increased levels of inflammatory markers in AD patients as well as findings from genome-wide association studies exploring the involvement of various single-nucleotide polymorphisms of genes related to neuroinflammation with the risk of developing AD. Inflammation in the brain has an important neuroprotective role during the acute-phase response; however, in the long term, neuroinflammation becomes detrimental. The activation of microglia and astrocytes triggers an innate immune response to release various pro-inflammatory mediators and toxic products such as reactive oxygen species and cytokines, which could collectively increase Aβproduction and tau hyper-phosphorylation, and thus contribute to disease progression and severity. Modulating the release of neuroinflammatory molecules and targeting pathological gliosis represent a valuable therapeutic approach and may have beneficial effects on the onset, progress, and severity of AD. In addition, external factors such as systemic inflammation, diabetes, and obesity could interfere with immunological processes of the brain and further promote disease progression; hence, the modulation of risk factors could lead to preventive strategies for AD.

We are pleased to invite you to participate in this Special Issue through research articles, comprehensive reviews, or short communications about neuroinflammation in AD, treatments targeting neuroinflammation, and related topics.

Prof. Dr. Amal Kaddoumi
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Alzheimer’s disease
  • neuroinflammation
  • drug development
  • microglia
  • astrocytes
  • cytokines
  • TREM2
  • risk factors
  • biomarkers

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Published Papers (2 papers)

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Research

18 pages, 6215 KiB  
Article
Clec7a Signaling in Microglia Promotes Synapse Loss Associated with Tauopathy
by Shubing Yang, Ji Wang, Yongkang Cao, Yibo Zhang, Zhuoran Sun, Pin Wan, Mingshan Pi, Qi Xiong, Xiji Shu, Xiaochuan Wang and Yiyuan Xia
Int. J. Mol. Sci. 2025, 26(7), 2888; https://doi.org/10.3390/ijms26072888 - 22 Mar 2025
Viewed by 541
Abstract
Alzheimer’s disease (AD) pathogenesis involves progressive synaptic degeneration, a process potentially driven by maladaptive microglial pruning activity. While synaptic loss is a hallmark of AD, the molecular signals triggering pathological microglia-mediated synaptic engulfment remain elusive. Clec7a—a key marker of disease-associated microglia (DAM)—is known [...] Read more.
Alzheimer’s disease (AD) pathogenesis involves progressive synaptic degeneration, a process potentially driven by maladaptive microglial pruning activity. While synaptic loss is a hallmark of AD, the molecular signals triggering pathological microglia-mediated synaptic engulfment remain elusive. Clec7a—a key marker of disease-associated microglia (DAM)—is known to activate spleen tyrosine kinase (SYK) signaling, enhancing Aβ phagocytosis and neuroprotective functions in 5×FAD models. However, its role in regulating synapse–microglia interactions under tauopathic conditions remains undefined. Our analysis revealed a progressive activation of the Clec7a–SYK signaling axis in the hippocampus of PS19 tauopathy mice, correlating with disease progression. Spatial mapping demonstrated a significant co-localization of Clec7a with hippocampal microglia, suggesting cell-autonomous signaling. The pharmacological inhibition of Clec7a achieved multimodal therapeutic effects by attenuating microglial hyperreactivity, suppressing neuroinflammatory cytokine release, and restoring physiological synaptic turnover. Mechanistically, we identified MD2 as a synaptic “eat-me” signal on tauopathy-related synapses, recruiting Clec7a+ microglia to drive aberrant synaptic elimination in PS19 mice. Strikingly, Clec7a blockade rescued hippocampal-dependent memory deficits in behavioral tests. These findings position Clec7a as a context-dependent therapeutic target, with inhibition strategies showing particular promise for tauopathy-related synaptic degeneration. Full article
(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer’s Disease and Related Dementias: 2nd Edition)
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21 pages, 8739 KiB  
Article
Vimentin Fragmentation and Its Role in Amyloid-Beta Plaque Deposition in Alzheimer’s Disease
by Lan Zhang, Ji Wang, Yalong Yan, Lihong Xiang, Xinyue Zhai, Lianmei Cai, Zhuoran Sun, Mingshan Pi, Qi Xiong, Hongyan Zhou, Yuran Gui, Xiaochuan Wang, Xiji Shu and Yiyuan Xia
Int. J. Mol. Sci. 2025, 26(7), 2857; https://doi.org/10.3390/ijms26072857 - 21 Mar 2025
Viewed by 308
Abstract
Intermediate filament protein vimentin (Vim) is a well-established marker for reactive astrocytes and has been closely associated with Alzheimer’s disease (AD). RNA sequencing data reveal elevated expression of Vim in AD brains, with its aggregation frequently observed around amyloid-β (Aβ) plaques. However, the [...] Read more.
Intermediate filament protein vimentin (Vim) is a well-established marker for reactive astrocytes and has been closely associated with Alzheimer’s disease (AD). RNA sequencing data reveal elevated expression of Vim in AD brains, with its aggregation frequently observed around amyloid-β (Aβ) plaques. However, the precise mechanisms by which Vim influences the aggregation or propagation of Aβ plaques remain unclear. In this study, we detected the upregulation of astrocytic Vim in AD brain tissue, with its co-localization around Aβ plaques. Asparagine endopeptidase (AEP), another molecule implicated in AD, was found to cleave Vim both in vitro and in vivo, including within human brain tissue. Mass spectrometry analysis confirmed that the AEP cleavage site on Vim is located at N283. We further investigated the in vivo cellular localization of Vim and observed that fragmented Vim, particularly the C-terminal fragment Vim 284–466, promotes apoptosis and disrupts the network structure that is essential for interaction with glial fibrillary acidic protein (GFAP). This disruption impairs astrocytic phagocytosis of exogenous Aβ, which is attributed to the reduced release of apolipoprotein E (ApoE) by astrocytes. The decrease in ApoE levels, in turn, diminishes the transport and clearance of Aβ. Conversely, mutation of the Vim N283 site (N283A) prevents AEP-mediated cleavage of Vim, preserves the GFAP network structure, restores ApoE levels, and reverses the effects on Aβ aggregation. Collectively, our findings elucidate the role of Vim fragmentation in Aβ plaque deposition and propose a potentially novel therapeutic strategy for Alzheimer’s disease. Full article
(This article belongs to the Special Issue Neuroinflammation in the Pathogenesis of Alzheimer’s Disease and Related Dementias: 2nd Edition)
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