Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Авг. 16, 2023

Abstract Background Microglia, the brain’s principal immune cells, have been implicated in pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences microglial function and transcriptomic programming described across development models AD, no studies comprehensively identified divergences that emerge aging mouse hippocampus. Further, existing AD generally develop pathology (amyloid plaques tau tangles) early life fail recapitulate aged brain environment associated with late-onset AD. Here, we examined compared translatomic effects young old murine hippocampal microglia. Methods Hippocampal tissue from C57BL6/N NuTRAP mice both sexes were collected at (5–6 month-old [mo]) (22–25 mo) ages. Cell sorting affinity purification techniques used isolate transcriptome translatome for RNA-sequencing differential expression analyses. Flow cytometry, qPCR, imaging approaches confirm findings. Results There marginal microglia, most differentially expressed genes (DEGs) restricted chromosomes. Both chromosomally autosomally encoded emerged aging. These DEGs age primarily female-biased enriched senescent disease-associated signatures. Normalized gene values can be accessed through searchable web interface ( https://neuroepigenomics.omrf.org/ ). Pathway analyses upstream regulators induced greater extent males, including inflammatory mediators IFNG, TNF, IL1B, as well AD-risk TREM2 APP. Conclusions data suggest female microglia adopt phenotypes hippocampus, even absence pathology, This sexually divergent phenotype may explain difference susceptibility progression case pathology. Future will need explore heterogeneity response determine how sex-specific (i.e., chromosomal or hormonal) elicit these effects.

Язык: Английский

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Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer’s disease model

Cell stem cell, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 1, 2024

Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's disease (AD) pathogenesis, effects on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons mouse hippocampus. Specifically, transplanted homozygous APOE4, isogenic APOE3, APOE-knockout (APOE-KO) iPSC-derived into hippocampus APOE3 or APOE4 knockin mice then depleted half mice. We found that APOE presence were for formation Aβ tau pathologies an isoform-dependent manner (APOE4 > APOE3). Single-cell RNA sequencing analysis identified two pro-inflammatory subtypes elevated MHC-II gene expression enriched neuron transplants. These findings highlight concerted APOE, especially pathogenesis.

Язык: Английский

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Glia Modulates Immune Responses in the Retina Through Distinct MHC Pathways

Glia, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

ABSTRACT Glia antigen‐presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. However, intricate mechanisms underlying their local coordination activation remain unclear. Our study integrates an animal model retinal injury, retrospective analysis human retinas, in vitro experiments gain insights into crucial role antigen presentation neuroimmunology during degeneration (RD), uncovering involvement various glial cells, notably Müller glia microglia. Glial act as sentinels, detecting antigens released interacting with T‐cells via MHC molecules, which essential for responses. Microglia function APCs Class II pathway, upregulating key molecules such Csf1r cytokines. In contrast, through I exhibiting upregulated processing genes promoting a CD8 + T‐cell response. Distinct cytokine signaling pathways, including TNF‐α IFN Type I, contribute balance. Human specimens corroborate these findings, demonstrating expression correlating degenerative changes. assays also confirmed differential migration responses activated microglia highlighting shaping milieu retina. summary, our emphasizes modulating response after insults parenchyma. Unraveling intricacies glia‐mediated RD is developing precise therapeutic interventions pathologies.

Язык: Английский

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A More Holistic Perspective of Alzheimer's Disease: Roles of Gut Microbiome, Adipocytes, HPA Axis, Melatonergic Pathway and Astrocyte Mitochondria in the Emergence of Autoimmunity

Frontiers in Bioscience-Landmark, Год журнала: 2023, Номер 28(12), С. 355 - 355

Опубликована: Дек. 28, 2023

Alzheimer's disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, pathophysiology has focused on two culprits, amyloid-β induced plaques and hyperphosphorylated tau associated tangles, with no significant treatment advance. This confounded by data showing be an endogenous antimicrobial that increased in a wide array of diverse medical conditions heightened inflammation. article reviews the wider bodies pertaining pathophysiology, highlighting role suppressed astrocyte mitochondrial function melatonergic pathway core hub driving neuronal loss dementia. It proposed over aging becomes dysregulated, at least partly mediated systemic processes involving 10-fold decrease pineal melatonin leading attenuated capacity night-time dampen residual daytime Suppressed also attenuates melatonin's inhibition glucocorticoid receptor nuclear translocation, thereby changing not only stress/hypothalamus-pituitary-adrenal (HPA) axis consequences but cortisol awakening response, which 'primes body for coming day'. Gut microbiome-derived butyrate inhibits well inducing pathway. prevents autocrine paracrine effects limiting levels effects. production induction lactate, decreasing metabolism The lactate melatonin, coupled suppression decreases mitophagy, major histocompatibility complex (MHC)-1. MHC-1 initiates chemoattraction CD8+ t cells, destruction being driven 'autoimmune'/'immune-mediated' processes. may therefore conceptualized initiated act astrocytes hub, leaving neurons deplete appropriate metabolic substrates co-ordinated antioxidants. culminates 'immune-mediated' cell death. Future research treatment/prevention implications are indicated.

Язык: Английский

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A single-cell transcriptomic atlas of the prefrontal cortex across the human lifespan

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 7, 2024

Abstract The dorsolateral prefrontal cortex is central to higher cognitive functions and particularly vulnerable age-related decline. To advance our understanding of the molecular mechanisms underlying brain development, maturation, aging, we constructed a detailed single-cell transcriptomic atlas human cortex, encompassing over 1.3 million nuclei from 284 postmortem samples spanning full lifespan (0-97 years). This reveals distinct phases activity: dynamic developmental period, stabilization during midlife, subtle yet coordinated changes in late adulthood. Modeling non-linear age trends across shows ten trajectories entire transcriptome all cell types, with notable findings neurons microglia, linked neurodevelopmental disorders Alzheimer’s disease risk, respectively. Moreover, excitatory exhibit convergence gene expression patterns lifespan, suggesting emergence common signature aging. Pseudotime analysis tracing progression cellular lineages throughout life key clusters that reflect as well their connection brain-related diseases. We uncover significant circadian rhythm reprogramming adulthood, characterized by disruption core clock rhythmicity new rhythmic patterns, within microglia oligodendrocytes. comprehensive provides baseline for transitions development through successful aging cortex.

Язык: Английский

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Analysis of secreted small extracellular vesicles from activated human microglial cell lines reveals distinct pro‐ and anti‐inflammatory proteomic profiles

PROTEOMICS, Год журнала: 2024, Номер 24(11)

Опубликована: Фев. 11, 2024

Abstract Microglia are a specialized population of innate immune cells located in the central nervous system. In response to physiological and pathological changes their microenvironment, microglia can polarize into pro‐inflammatory or anti‐inflammatory phenotypes. A dysregulation pro‐/anti‐inflammatory balance is associated with many pathophysiological brain Therefore, between polarization be potential biomarker for various pathologies. non‐invasive method detecting patients would have promising clinical applications. Here, we perform proteomic analysis small extracellular vesicles (sEVs) derived from identify sEVs biomarkers indicative phenotypic changes. were isolated cell lines under different inflammatory conditions analyzed by proteomics liquid chromatography mass spectrometry. Our findings provide roles that could related pathogenesis diseases.

Язык: Английский

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Microglial apolipoprotein E particles contribute to neuronal senescence and synaptotoxicity

iScience, Год журнала: 2024, Номер 27(6), С. 110006 - 110006

Опубликована: Май 16, 2024

Apolipoprotein E (apoE) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit substantial upregulation apoE AD-associated circumstances, despite astrocytes being primary source expression and secretion brain. Although astrocytic brain has been extensively investigated, it remains unclear that whether how particles generated from microglia differ biological characteristic function. Here, we demonstrate differences size between astrocytes. Microglial impair neurite growth synapses, promote neuronal senescence, whereas depletion GPNMB (glycoprotein non-metastatic melanoma protein B) microglial mitigated these deleterious effects. In addition, human APOE4-expressing are more neurotoxic than APOE3-bearing microglia. For first time, results offer concrete evidence produced by involved senescence toxicity.

Язык: Английский

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Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer’s Disease Model

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 14, 2023

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's Disease (AD) pathogenesis, effects on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such utilizing microglial depletion a chimeric model with human neurons mouse hippocampus. Specifically, transplanted homozygous APOE4, isogenic APOE3, APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived into hippocampus APOE3 or APOE4 knock-in mice, depleted half mice. We found that APOE presence were important for formation Aβ tau pathologies an isoform-dependent manner (APOE4 > APOE3). Single-cell RNA-sequencing analysis identified two pro-inflammatory subtypes high MHC-II gene expression are enriched mice neuron transplants. These findings highlight concerted roles APOE, especially pathogenesis.

Язык: Английский

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Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 10, 2023

Microglia, the brain's principal immune cells, have been implicated in pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences microglial function and transcriptomic programming described across development models AD, no studies comprehensively identified divergences that emerge aging mouse hippocampus. Further, existing AD generally develop pathology (amyloid plaques tau tangles) early life fail recapitulate aged brain environment associated with late-onset AD. Here, we examined compared translatomic effects young old murine hippocampal microglia.

Язык: Английский

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Glia-Mediated Antigen Presentation In The Retina During Degeneration

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 25, 2024

ABSTRACT Glia antigen-presenting cells (APCs) are pivotal regulators of immune surveillance within the retina, maintaining tissue homeostasis and promptly responding to insults. The intricate mechanisms underlying their local coordination activation remain unclear. Our study integrates an animal model retinal injury, retrospective analysis human retinas, in vitro experiments elucidate insights into role antigen presentation neuroimmunology during degeneration, uncovering involvement various glial cells, notably Müller glia, microglia. Glial act as sentinels, detecting antigens released degeneration interacting with T-cells via MHC molecules, which essential for responses. Microglia function APCs class II pathway, upregulating key molecules such Csf1r cytokines. In contrast, atypical through I exhibiting upregulated processing genes promoting a CD8 + T-cell response. Distinct cytokine signaling pathways, including TNF-α IFN, contribute balance. Human specimens corroborate these findings, demonstrating expression correlating degenerative changes. assays also confirmed differential migration responses activated microglia highlighting shaping milieu retina. These emphasize complex interplay between T-cells, influencing inflammatory environment potentially modulating processes. summary, our emphasizes response after insults parenchyma. Thus, unraveling intricacies glia-mediated is developing precise therapeutic interventions pathologies.

Язык: Английский

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