Microglia and amyloid plaque formation in Alzheimer's disease – Evidence, possible mechanisms, and future challenges

Journal of Neuroimmunology, Journal Year: 2024, Volume and Issue: 390, P. 578342 - 578342

Published: April 5, 2024

Alzheimer's disease (AD) is a neurodegenerative characterized by cognitive decline that severely affects patients and their families. Genetic environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. factors for late-onset AD (LOAD), which accounts most cases, are predominantly implicated in microglial immune cell functions. As such, microglia play major role amyloid beta (Aβ) plaque (the pathological hallmark of AD) formation. This review aims provide an overview current knowledge regarding Aβ formation, well impact on morphological functional diversity plaques. Based this discussion, we seek identify challenges opportunities field with potential therapeutic implications.

Language: Английский

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Autophagy–lysosomal-associated neuronal death in neurodegenerative disease

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Sept. 11, 2024

Language: Английский

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Early Alzheimer’s Disease with frequent neuritic plaques harbors neocortical tau seeds distinct from primary age-related tauopathy

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 21, 2025

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for diagnosis Alzheimer's Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all species equally pathogenic raises question whether unidentified modifications augment seeding activity neurodegeneration AD. We investigated how biochemical relate to clinicopathological outcomes a cohort 38 patients Braak-matched AD neuropathologic change (ADNC) or primary age-related tauopathy (PART), 3R/4R identical filament core structure ADNC but little no Aβ deposition. comprehensively measured histologic density, using real-time quaking induced conversion (RT-QuIC) amplification assays, select post-translational (PTMs) (i.e. pT217, pS202/T205, & C-terminal epitopes) hippocampus neocortex. Even cases without overt neocortical neuropathology, substantial hippocampal occurred both PART predicted region-specific performance longitudinal decline. Notably, PTM profiles were associated neuritic plaque density differentiated Our data indicate meaningfully disease trajectory, potentially explaining more severe dysfunction observed late-stage versus PART. Abnormal, misfolded proteins found Tauopathies, suggesting pathogenic. Here, authors show modification two tauopathies.

Language: Английский

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The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Abstract INTRODUCTION Plaques are a hallmark feature of Alzheimer's disease (AD). We found that the loss mucosal‐associated invariant T (MAIT) cells and their antigen‐presenting molecule MR1 caused delay in plaque pathology development AD mouse models. However, it remains unknown how this axis is impacting dystrophic neurites. METHODS Brain tissue from 5XFAD mice those deficient (MR1 KO), were analyzed for neurites, amyloid plaques, synapses via immunofluorescence, RNA sequencing, enzyme‐linked immunosorbent assay, western blot. RESULTS In 8‐month‐old 5XFAD/MR1 KO mice, there was reduced expression lysosomal‐associated membrane protein 1, ubiquitin, n ‐terminal precursor hippocampus compared to ( P < 0.05). also had less insoluble beta 40 0.001) higher levels postsynaptic density 95 0.01) hippocampus. DISCUSSION Our data contribute additional mechanistic insight into detrimental role MR1/MAIT cell development. Highlights lacking innate immune (mucosal‐associated T) (5XFAD/MR1 KO) have numbers neurite markers at 8 months age. Hippocampal transcriptional analyses showed genes encoding classical mice. increased post‐synaptic marker, 95, than did MR1+

Language: Английский

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Zim4rv: an R package to modeling zero-inflated count phenotype on regional-based rare variants

BMC Bioinformatics, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 16, 2025

With the advance of next-generation sequencing, various gene-based rare variant association tests have been developed, particularly for binary and continuous phenotypes. In contrast, fewer methods are available traits not following binomial or normal distributions. To address this, we previously proposed a set burden- kernel-based count data zero-inflated Poisson (ZIP) distributions, referred to as ZIP-b ZIP-k tests. We sought extend accommodate negative distribution implemented these in new R package. introduce ZIM4rv, an package designed analyze variants with counts outcomes. Our offers two novel models developed by our team: tests, newly derived Negative Binomial Burden Kernel Test (ZINB-b, ZINB-k). Additionally, include ad-hoc two-stage analysis, testing zero non-zero outcome outcome, respectively. showcase utility platform, applied this program neuritic plaque from ROSMAP cohort. The ZIM4rv presents integrated workflow conducting on data.

Language: Английский

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The potential link between the development of Alzheimer’s disease and osteoporosis

Biogerontology, Journal Year: 2025, Volume and Issue: 26(1)

Published: Jan. 20, 2025

Language: Английский

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Microglia aggregates define distinct immune and neurodegenerative niches in Alzheimer's disease hippocampus

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: Feb. 15, 2025

Abstract In Alzheimer’s disease (AD), microglia form distinct cellular aggregates that play critical roles in progression, including Aβ plaque-associated (PaM) and the newly identified coffin-like (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM enriched pyramidal layer of CA2/CA1 hippocampal subfields, where they frequently engulf neurons associate tau-positive tangles phosphorylated α-synuclein. To elucidate role these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry confocal microscopy, to comprehensively map characterise their morphological molecular signatures, as well neuropathological astrocytic microenvironments, AD control post-mortem samples. PaM-associated astrocytes exhibited signatures related complement system pathways, ErbB signalling, metabolic neurodegenerative processes. contrast, displayed markers protein degradation immune signalling STING, TGF-β, NF-κB. While no direct association between CD8 + T cells either type was observed, CD163 perivascular macrophages were incorporated into PaM. These findings provide novel insights heterogeneity responses, particular interactions infiltrating cells, shed light on specific hotspots implications for deterioration AD.

Language: Английский

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Computational and functional prioritization identifies genes that rescue behavior and reduce tau protein in fly and human cell models of Alzheimer disease

The American Journal of Human Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Visualization of Apolipoprotein E-Binding Amyloid Plaques in Postmortem Alzheimer’s Disease Brains Using a Novel Fluorescent Probe THK-5320

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: 16(9), P. 1804 - 1814

Published: April 28, 2025

(E)-2-(4-(dimethylamino)styryl)-N,N-dimethylquinolin-6-amine) (THK-5320) is a unique fluorescent compound that recognizes apolipoprotein E (ApoE)-binding amyloid plaques in postmortem human brain sections. To understand the distinctive characteristics of THK-5320 chemically and biologically, its fluorescence properties were investigated, association wavelength with plaque subtypes isoforms was explored. Blue visualized consistent those anti-amyloid-β1-16/amyloid-βN3pE-stained antibodies, whereas red an ApoE-stained antibody sections from patients Alzheimer's disease. In contrast, positron emission tomography (PET) tracer PiB derivative did not show significant signals ApoE-binding plaques, correlated well amyloid-βN3pE-positive plaques. Thus, may detect conventional PET probes cannot detect. Multispectral imaging could be useful tool to better role ApoE pathology.

Language: Английский

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Annexin A6 membrane repair protein protects against amyloid-induced dystrophic neurites and tau phosphorylation in Alzheimer’s disease model mice

Acta Neuropathologica, Journal Year: 2025, Volume and Issue: 149(1)

Published: May 24, 2025

Language: Английский

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