The neuroimmune axis of Alzheimer’s disease

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Jan. 26, 2023

Abstract Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial pathological roles for innate immune genes cells, peripheral cells such as T which can infiltrate brain either ameliorate or exacerbate AD neuropathogenesis. These findings support neuroimmune axis of AD, in interplay adaptive systems inside outside critically impacts etiology pathogenesis AD. In this review, we discuss complexities neuropathology at levels genetics cellular physiology, highlighting signaling pathways associated risk interactions among brain. We emphasize role mechanisms by monocytes, influence neuropathology, microglial clearance amyloid-β peptide, key component plaque cores, pro-inflammatory cytotoxic activity microglia, astrogliosis, their vasculature. Finally, review challenges outlook establishing immune-based therapies treating preventing

Language: Английский

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Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: June 24, 2021

While the central nervous system compromises 2% of our body weight, it harbors up to 25% body's cholesterol. Cholesterol levels in brain are tightly regulated for physiological function, but mounting evidence indicates that excessive cholesterol accumulates Alzheimer's disease (AD), where may drive AD-associated pathological changes. This seems especially relevant late-onset AD, as several major genetic risk factors functionally associated with metabolism. In this review we discuss different systems maintain metabolism healthy brain, and how dysregulation these processes can lead, or contribute to, disease. We will also AD-risk genes might impact downstream AD pathology. Finally, address outstanding questions field recent technical advances CRISPR/Cas9-gene editing induced pluripotent stem cell (iPSC)-technology aid study problems.

Language: Английский

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Beyond Activation: Characterizing Microglial Functional Phenotypes

Cells, Journal Year: 2021, Volume and Issue: 10(9), P. 2236 - 2236

Published: Aug. 28, 2021

Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, phagocytic viewed “activated”. In aged human brains, a fourth, morphologically novel state has described, i.e., dystrophic microglia, which are thought to be senescent cells. Since not replenished by blood-borne mononuclear under physiological circumstances, they seem an “expiration date” limiting their capacity phagocytose support neurons. Identifying factors that drive microglial aging may thus helpful delay onset neurodegenerative diseases, such Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation revealed regional-, age- sex-dependent differences population, growing number studies demonstrate various expression profiles defining subpopulations. Given heterogeneity pathologic central nervous system, need accurately describing morphology patterns becomes increasingly important. Here, we review commonly used markers fluctuations health disease, with focus on IBA1 low/negative can found individuals liver disease.

Language: Английский

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Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(1), P. 4 - 17

Published: Jan. 1, 2022

Language: Английский

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Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL‐1β drives amplified responses in primed astrocytes and neuronal network dysfunction

Alzheimer s & Dementia, Journal Year: 2021, Volume and Issue: 17(10), P. 1735 - 1755

Published: June 3, 2021

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors this vulnerability require elucidation. Using APP/PS1 mice AD brain, we studied secondary investigate hypersensitive responses in microglia, astrocytes, neurons, human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, microglia were primed, facilitating exaggerated interleukin-1β (IL-1β) subsequent LPS stimulation. Astrocytes primed produce chemokine intrahippocampal IL-1β. Systemic triggered microglial IL-1β, astrocytic chemokines, IL-6, acute dysfunction, whereas IL-1β disrupted hippocampal gamma rhythm, all selectively mice. Brains from patients with infection showed elevated IL-6 levels. Therefore, leaves the vulnerable inflammation at microglial, astrocytic, neuronal, levels, amplifies neuroinflammatory cytokine synthesis humans. Exacerbation of neuroinflammation deleterious outcomes like accelerated progression merits careful investigation

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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Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(7), P. 963 - 974

Published: May 25, 2023

Language: Английский

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Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer’s disease

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(7), P. 1135 - 1153.e8

Published: July 1, 2022

Language: Английский

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Human neural cell type‐specific extracellular vesicle proteome defines disease‐related molecules associated with activated astrocytes in Alzheimer's disease brain

Journal of Extracellular Vesicles, Journal Year: 2022, Volume and Issue: 11(1)

Published: Jan. 1, 2022

In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced pluripotent stem cell-derived neural cell types (excitatory neurons, astrocytes, microglia-like cells, oligodendrocyte-like cells). Novel type-specific EV protein markers then identified for excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), cells (ITGAM, LCP1), (LAMP2, FTH1), as well 16 pan-EV marker candidates, including integrins annexins. To further demonstrate how cell-type-specific may be Alzheimer's (AD), we performed co-expression network analysis conducted type assessments proteomes brain-derived control, mild cognitive impairment, AD cases. A module enriched astrocyte-specific was most significantly associated with pathology suggesting an important role The hub this module, integrin-β1 (ITGB1), found to elevated total brain β-amyloid tau load independent cohorts. Thus, our study provides a featured framework rich resource future analyses functions diseases manner.

Language: Английский

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112196 - 112196

Published: March 1, 2023

The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept immunometabolism. Here, we combined bulk, single-cell, spatial transcriptomics cell-specific spatially resolved analyses in mice expressing human APOE to systematically address role across age, neuroinflammation, AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes APOE4 glial transcriptome, specifically subsets metabolically distinct microglia enriched brain during aging or following an inflammatory challenge. display increased Hif1α expression disrupted tricarboxylic acid (TCA) cycle are inherently pro-glycolytic, while mass spectrometry imaging highlight E4-specific response amyloid characterized by widespread alterations lipid metabolism. Taken together, our emphasize central for regulating microglial immunometabolism provide valuable, interactive resources discovery validation research.

Language: Английский

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