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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Beyond Amyloid and Tau: The Critical Role of Microglia in Alzheimer’s Disease Therapeutics

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 279 - 279

Published: Jan. 23, 2025

Alzheimer’s disease (AD) is traditionally viewed through the lens of amyloid cascade hypothesis, implicating amyloid-beta and tau protein aggregates as main pathological culprits. However, burgeoning research points to brain’s resident immune cells, microglia, critical players in AD pathogenesis, progression, potential therapeutic interventions. This review examines dynamic roles microglia within intricate framework AD. We detail involvement these cells neuroinflammation, explaining how their activation response fluctuations may influence trajectory. further elucidate complex relationship between pathology. study highlights dual nature which contribute both aggregation clearance protein. Moreover, an in-depth analysis interplay unveils significant, yet often overlooked, impact this interaction on neurodegeneration Shifting from conventional approaches, we assess current treatments primarily targeting introduce novel strategies that involve manipulating microglial functions. These innovative methods herald a paradigm shift management Finally, explore field precision diagnosis pursuit robust biomarkers. underline more profound comprehension biology could enrich essential areas, potentially paving way for accurate diagnostic tools tailored treatment strategies. In conclusion, expands perspective pathology treatment, drawing attention multifaceted microglia. As continue enhance our understanding microglial-focused interventions emerge promising frontier bolster arsenal fight against

Language: Английский

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Targeting Microglia in Alzheimer’s Disease: Pathogenesis and Potential Therapeutic Strategies

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 833 - 833

Published: July 11, 2024

Microglia, as resident macrophages in the central nervous system, play a multifunctional role pathogenesis of Alzheimer’s disease (AD). Their clustering around amyloid-β (Aβ) deposits is core pathological feature AD. Recent advances single-cell RNA sequencing (scRNA-seq) and single-nucleus (snRNA-seq) have revealed dynamic changes microglial phenotypes over time across different brain regions during aging AD progression. As advances, microglia primarily exhibit impaired phagocytosis Aβ tau, along with release pro-inflammatory cytokines that damage synapses neurons. Targeting has emerged potential therapeutic approach for Treatment strategies involving can be broadly categorized into two aspects: (1) enhancing function: This involves augmenting their phagocytic ability against cellular debris (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches treatment garnered attention. Additionally, natural products show promise beneficial effects suppressing inflammatory responses. Clarifying dynamics, understanding roles, novel will advance our fight

Language: Английский

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Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 5, 2024

Abstract The role of microglia in the amyloid cascade Alzheimer’s disease (AD) is debated due to conflicting findings. Using a genetic and pharmacological approach we demonstrate that depletion before amyloid-β (Aβ) plaque deposition, leads reduction numbers neuritic dystrophy, confirming their initiation. Transplanting human restores Aβ formation. While reduces insoluble levels, soluble concentrations stay consistent, challenging view clear Aβ. In later stages, microglial decreases compaction increases suggesting protective role. Human with TREM2 R47H/R47H mutation exacerbate pathology, emphasizing importance non-reactive initiation cascade. Adaptive immune ( Rag2 -/- ) does not affect microglia’s impact on These findings clarify reports, identifying as key drivers raise questions about optimal therapeutic strategies for AD.

Language: Английский

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Serum proteomics reveals early biomarkers of Alzheimer's disease: The dual role of <i>APOE-ε4 </i>

BioScience Trends, Journal Year: 2025, Volume and Issue: 19(1), P. 1 - 9

Published: Jan. 22, 2025

Alzheimer's disease (AD), the leading cause of dementia, significantly impacts global public health, with cases expected to exceed 150 million by 2050. Late-onset (LOAD), predominantly influenced APOE-ε4 allele, exhibits complex pathogenesis involving amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), neuroinflammation, and blood-brain barrier (BBB) disruption. Proteomics has emerged as a pivotal technology in uncovering molecular mechanisms identifying biomarkers for early diagnosis intervention AD. This paper reviews genetic roles pathology AD, including its effects on Aβ aggregation, tau phosphorylation, BBB integrity. Additionally, it highlights recent advances serum proteomics, revealing APOE-ε4-dependent independent protein signatures potential Despite technological progress, challenges such population diversity, standardization, distinguishing AD-specific remain. Directions future research emphasize multicenter longitudinal studies, multi-omics integration, clinical translation proteomic findings enable detection AD personalized treatment strategies. hold promise improving patient outcomes reducing burden.

Language: Английский

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Digestive exophagy as a novel mechanism of amyloid-β degradation by microglial lysosomes

Trends in Neurosciences, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

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Temporal Transcriptomic Analysis of Periodontal Disease Progression and Its Molecular Links to Systemic Diseases

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1998 - 1998

Published: Feb. 25, 2025

Periodontal disease, a prevalent oral inflammatory condition, is implicated in exacerbating systemic diseases. However, the molecular mechanisms underlying this association remain unclear. In study, we performed RNA sequencing of gingival tissue samples collected from mouse model periodontal disease at multiple time points to investigate dynamic transcriptomic changes during progression. Our analysis revealed distinct temporal gene expression patterns associated with key and immune response pathways. These findings suggest stepwise progression process, potentially contributing inflammation through shared signaling networks. We further identified specific genes pathways that may mediate bidirectional relationship between conditions such as cardiovascular diabetes. By elucidating dynamics study provides insights into pathogenesis its implications. It identifies potential biomarkers therapeutic targets for local management.

Language: Английский

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Decoding microglial functions in Alzheimer’s disease: insights from human models

Trends in Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

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Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer’s disease mouse model

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 20, 2025

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) an AD-associated factor. Increased Asrij levels in brains AD patients mouse models are linked to severity neurodegeneration. However, contribution progression whether reducing sufficient mitigate Aβ pathology vivo unclear. To explore impact on pathology, we deleted asrij APP/PS1 model analyzed effects hallmarks. We used Morris water maze open field test assess behavioral performance. Using immunohistochemistry biochemical analyses, evaluated plaque load, neuronal synaptic damage, gliosis. Further, utilized confocal microscopy imaging, flow cytometry, RNA sequencing analysis comprehensively investigate changes microglial responses upon depletion. depletion ameliorates cognitive impairments, deposition, reactive astrogliosis mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation decreased phagocytic Transcriptomic analyses reveal upregulation energy metabolism pathways downregulation innate immunity inflammatory Mechanistically, loss increases mitochondrial activity impedes acquisition pro-inflammatory disease-associated (DAM) state. Reduced proinflammatory cytokines STAT3 NF-κB activation indicate protective microglia. Taken together, our results suggest that increased reported AD, may suppress metabolic promote activation, thereby exacerbating pathology. In summary, show gliosis, improves performance mice. This supports exacerbates critical for development DAM promotes neuroinflammatory signaling microglia, thus restricting neuroprotective responses. Hence, this context help retard AD. Our work positions as molecular regulator links dysfunction pathogenesis.

Language: Английский

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Interplay of Neuroinflammation and Gut Microbiota Dysbiosis in Alzheimer’s Disease Using Diffusion Kurtosis Imaging Biomarker in 3 × Tg-AD Mouse Models

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

The relationship between alterations in brain microstructure and dysbiosis of gut microbiota Alzheimer's disease (AD) has garnered increasing attention, although the functional implications these changes are not yet fully elucidated. This research examines how neuroinflammation, systemic inflammation, interact male 3 × Tg-AD B6129SF1/J wild-type (WT) mice at 6 months-old (6-MO) 12 (12-MO). Employing a combination behavioral assessments, diffusion kurtosis imaging (DKI), profiling, cytokine analysis, short-chain fatty acids (SCFAs), immunohistochemistry, we explored progression AD-related pathology. Significant memory impairments AD both assessed ages were correlated with altered DKI parameters that suggest neuroinflammation microstructural damage. We observed elevated levels pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα, IFN-γ, serum, which associated increased activity microglia astrocytes regions critical for memory. Although analysis did reveal significant alpha diversity, it show notable differences beta diversity diminished Firmicutes/Bacteroidetes (F/B) ratio 12-MO. Furthermore, reduction six kinds SCFAs identified two time points 6-MO 12-MO, indicating widespread disruption microbial metabolism. These findings underscore complex bidirectional inflammation AD, highlighting gut-brain axis crucial factor progression. study emphasizes potential integrating metrics, SCFA to enhance our understanding pathology identify new therapeutic targets.

Language: Английский

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