The Amyloid-β Pathway in Alzheimer’s Disease

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(10), P. 5481 - 5503

Published: Aug. 30, 2021

Abstract Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at center of Alzheimer’s disease (AD) pathophysiology. While detailed mechanisms and spatial-temporal dynamics leading to synaptic failure, neurodegeneration, clinical onset are still under intense investigation, established biochemical alterations Aβ cycle remain core biological hallmark AD promising targets for development disease-modifying therapies. Here, we systematically review update vast state-of-the-art literature science with evidence from basic research studies human genetic multi-modal biomarker investigations, which supports a crucial role dyshomeostasis pathophysiological dynamics. We discuss highlighting differentiated interaction distinct species other AD-related mechanisms, such as tau-mediated, neuroimmune inflammatory changes, well neurochemical imbalance. Through lens latest multimodal vivo biomarkers AD, this cross-disciplinary examines compelling hypothesis- data-driven rationale Aβ-targeting therapeutic strategies early treatment AD.

Language: Английский

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Role of neuroinflammation in neurodegeneration development

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: July 12, 2023

Abstract Studies in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis, Huntington’s so on, have suggested that inflammation is not only a result of neurodegeneration but also crucial player this process. Protein aggregates which are very common pathological phenomenon can induce neuroinflammation further aggravates protein aggregation neurodegeneration. Actually, even happens earlier than aggregation. Neuroinflammation induced by genetic variations CNS cells or peripheral immune may deposition some susceptible population. Numerous signaling pathways range been to be involved the pathogenesis neurodegeneration, although they still far from being completely understood. Due limited success traditional treatment methods, blocking enhancing inflammatory considered promising strategies for therapy many them got exciting results animal models clinical trials. Some them, few, approved FDA usage. Here we comprehensively review factors affecting major pathogenicity sclerosis. We summarize current strategies, both clinic, diseases.

Language: Английский

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Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 23 - 39

Published: Oct. 31, 2022

Language: Английский

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Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease

Neuron, Journal Year: 2022, Volume and Issue: 110(11), P. 1788 - 1805.e10

Published: April 4, 2022

Language: Английский

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Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4365 - 4385.e27

Published: Sept. 1, 2023

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas aged human prefrontal cortex covering 2.3 million cells from postmortem brain samples 427 individuals with varying degrees AD pathology impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed coordinated increase cohesin complex DNA damage response factors in neurons oligodendrocytes, uncovered genes pathways associated high function, dementia, resilience to pathology. Furthermore, selectively vulnerable somatostatin inhibitory subtypes depleted AD, discovered two distinct groups that were more abundant preserved function late life, link

Language: Английский

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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?

The Journal of Experimental Medicine, Journal Year: 2021, Volume and Issue: 218(9)

Published: July 22, 2021

Alzheimer's disease (AD) is characterized by extracellular aggregates of amyloid β peptides, intraneuronal tau aggregates, and neuronal death. This pathology triggers activation microglia. Because variants genes expressed in microglia correlate with AD risk, microglial response to plausibly impacts course. In mouse models, single-cell RNA sequencing (scRNA-seq) analyses delineated this as progressive conversion homeostatic into disease-associated (DAM); additional reactive populations have been reported other models neurodegeneration neuroinflammation. We review all these signatures, highlighting four fundamental patterns: DAM, IFN-microglia, MHC-II microglia, proliferating propose that are either just one or a combination, depending on the clustering strategy applied model. further single-nucleus (snRNA-seq) data from human specimens discuss reasons for parallels discrepancies between transcriptional profiles. Finally, we outline future directions delineating impact pathogenesis.

Language: Английский

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Molecular and spatial signatures of mouse brain aging at single-cell resolution

Cell, Journal Year: 2022, Volume and Issue: 186(1), P. 194 - 208.e18

Published: Dec. 28, 2022

The diversity and complex organization of cells in the brain have hindered systematic characterization age-related changes its cellular molecular architecture, limiting our ability to understand mechanisms underlying functional decline during aging. Here, we generated a high-resolution cell atlas aging within frontal cortex striatum using spatially resolved single-cell transcriptomics quantified gene expression spatial major types these regions over mouse lifespan. We observed substantially more pronounced state, expression, non-neuronal neurons. Our data revealed signatures glial immune activation aging, particularly enriched subcortical white matter, identified both similarities notable differences cell-activation patterns induced by systemic inflammatory challenge. These results provide critical insights into inflammation brain.

Language: Английский

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Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease

Cells, Journal Year: 2022, Volume and Issue: 11(12), P. 1885 - 1885

Published: June 10, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many brain’s immunological cells, specifically microglia astrocytes, are involved in AD pathogenesis. Cells innate immune system play an essential role eliminating pathogens but also regulate brain homeostasis AD. When activated, cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, PANoptosis. The often results release proinflammatory cytokines propagate response eliminate Aβ aggregated Tau proteins. However, chronic neuroinflammation, which result from death, has been linked to diseases worsen Therefore, must be tightly balanced appropriately clear these AD-related structural abnormalities without inducing neuroinflammation. In this review, we discuss responses, inflammatory cytokine secretion as they relate Therapeutic strategies targeting mechanisms will critical consider for future preventive or palliative treatments

Language: Английский

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Disease-associated oligodendrocyte responses across neurodegenerative diseases

Cell Reports, Journal Year: 2022, Volume and Issue: 40(8), P. 111189 - 111189

Published: Aug. 1, 2022

Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct oligodendrocytes from single-cell RNA sequencing (RNA-seq) mouse models Alzheimer's (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, genes influencing survival), IFN (associated interferon response genes). Spatial analysis disease-associated (DAOs) cuprizone model reveals that are established outside lesion area during demyelination repopulates remyelination. Independent meta-analysis human single-nucleus RNA-seq datasets transcriptional responses MS share features models. In contrast, signature observed AD is largely those mice. This catalog (http://research-pub.gene.com/OligoLandscape/) will be important to understand progression develop therapeutic interventions.

Language: Английский

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Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

Alzheimer s Research & Therapy, Journal Year: 2021, Volume and Issue: 13(1)

Published: June 9, 2021

Abstract Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this remain unclear. A better understanding causative processes by which COVID-19 may lead to essential developing preventive and therapeutic interventions. Methods In study, we conducted a network-based, multimodal omics comparison neurologic complications. We constructed virus-host interactome from protein-protein interaction assay CRISPR-Cas9-based genetic results compared network-based relationships therein with those known neurological manifestations using network proximity measures. also investigated transcriptomic profiles (including single-cell/nuclei RNA-sequencing) Alzheimer’s disease (AD) marker genes patients infected COVID-19, as well prevalence entry factors in brains AD not SARS-CoV-2. Results found significant between neuroinflammation brain microvascular injury pathways are implicated AD. detected aberrant expression biomarkers cerebrospinal fluid blood COVID-19. While analyses showed relatively low human brain, neuroinflammatory changes were pronounced. addition, single-nucleus that host ( BSG FURIN ) antiviral defense LY6E , IFITM2 IFITM3 IFNAR1 was elevated endothelial cells healthy controls relative neurons other cell types, suggesting possible role COVID-19-mediated impairment. Overall, individuals risk allele APOE E4/E4 displayed reduced E3/E3 individuals. Conclusion Our suggest mechanistic overlap centered on injury. These help improve our COVID-19-associated provide guidance future development or treatment interventions, although causal relationship need investigations.

Language: Английский

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