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Autophagy restricts senescence and enables microglia to engage amyloid plagues in neuroprotection

ABSTRACT: Autophagy restricts senescence and enables microglia to engage amyloid plagues in neuroprotection

PROVIDER: PRJNA793906 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17418008_1.fastq.gz	Fastqsanger.gz
	SRR17418008_2.fastq.gz	Fastqsanger.gz
	SRR17418009_1.fastq.gz	Fastqsanger.gz
	SRR17418009_2.fastq.gz	Fastqsanger.gz
	SRR17418010_1.fastq.gz	Fastqsanger.gz

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Autophagy restricts senescence and enables microglia to engage amyloid plagues in neuroprotection

Project description:Microglia are essential to maintain brain homeostasis, but when dysregulated, exert pathogenic functions in Alzheimer’s disease (AD). Recent evidence has implicated senescent/dystrophic microglia in the pathological process of AD. Whether microglial senescence is a cause or consequence of AD pathogenesis however is unclear. Here we report that autophagy, a lysosomal degradation pathway, restricts cellular senescence of microglia and confer neuroprotection in AD mouse model. Autophagy-deficient microglia show hallmarks of cellular senescence evidenced by reduced proliferation, increased Cdkn1a/p21Cip, dystrophy, and typical secretory phenotype. While disease-associated microglia (DAM) surrounding amyloid plaques exhibit heightened autophagy, autophagy deficient, senescent microglia (SAM) disengage from and thus fail to limit the diffusive amyloid plaques, causing enhanced tau phosphorylation and neurotoxicity in AD model. Treatment of senolytic drugs removes senescent microglia and alleviates neuropathology. Our study demonstrates a causal role of autophagy impairment in microglial senescence and neurotoxicity and suggests therapeutic potential of senolytic treatment for AD.

2023-04-24 | GSE192964 | GEO

Autophagy enables microglia to engage amyloid plaques and prevents microglial senescence.

Project description:Dysfunctional autophagy has been implicated in the pathogenesis of Alzheimer's disease (AD). Previous evidence suggested disruptions of multiple stages of the autophagy-lysosomal pathway in affected neurons. However, whether and how deregulated autophagy in microglia, a cell type with an important link to AD, contributes to AD progression remains elusive. Here we report that autophagy is activated in microglia, particularly of disease-associated microglia surrounding amyloid plaques in AD mouse models. Inhibition of microglial autophagy causes disengagement of microglia from amyloid plaques, suppression of disease-associated microglia, and aggravation of neuropathology in AD mice. Mechanistically, autophagy deficiency promotes senescence-associated microglia as evidenced by reduced proliferation, increased Cdkn1a/p21Cip1, dystrophic morphologies and senescence-associated secretory phenotype. Pharmacological treatment removes autophagy-deficient senescent microglia and alleviates neuropathology in AD mice. Our study demonstrates the protective role of microglial autophagy in regulating the homeostasis of amyloid plaques and preventing senescence; removal of senescent microglia is a promising therapeutic strategy.

| S-EPMC10950302 | biostudies-literature

Modulation of gene expression by complement protein C1q in amyloid-beta injured neurons

Project description:Complement protein C1q is induced after injury in the brain and during Alzheimer's disease and has been shown to protect against amyloid-beta induced neuronal death. In this study, we used microarray approach to identify the pathways modulated by C1q that are associated with neuroprotection. Immature rat cortical primary neurons are treated with fibrillar amyloid-beta peptides and/or C1q for 3h before RNA extraction and hybridization on rat Affymetrix microarrays. Supplementary file: Processed/normalized, probe-level signal intensities from neurons treated with amyloid-beta or C1q. Median signal intensity used as global normalization method, done with JMP genomics (v5.0) software.

2012-12-21 | E-GEOD-28886 | biostudies-arrayexpress

ENGAGE Transcriptomics Flagship

Project description:ENGAGE Transcriptomics Flagship

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Modulation of gene expression by complement protein C1q in amyloid-beta injured neurons

2012-12-21 | GSE28886 | GEO

Engage Project

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The Alzheimer’s disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology [snRNA-seq]

Project description:The Alzheimer’s disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology [snRNA-seq]

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Nfe2l3 promotes neuroprotection and long-distance axon regeneration after injury in vivo [bulkRNA-seq]

Project description:Nuclear factor erythroid 2 like (Nfe2l) gene family members 1-3 mediate cellular response to oxidative stress, including in the central nervous system (CNS). However, neuronal functions of Nfe2l3 are unknown. Here, we comparatively evaluated expression of Nfe2l1, Nfe2l2, and Nfe2l3 in singe cell RNA-seq (scRNA-seq)-profiled cortical and retinal ganglion cell (RGC) CNS projection neurons, investigated whether Nfe2l3 regulates neuroprotection and axon regeneration after CNS injury in vivo, and characterized a gene network associated with Nfe2l3 in neurons. We showed that, Nfe2l3 expression transiently peaks in developing immature cortical and RGC projection neurons, but is nearly abolished in adult neurons and is not upregulated after injury. Furthermore, within the retina, Nfe2l3 is enriched in RGCs, whereas Nfe2l1 and Nfe2l2 are expressed robustly in other retinal cell types as well, and are also upregulated after injury. We also found that, expressing Nfe2l3 in injured RGCs through localized intralocular viral vector delivery promotes neuroprotection and long-distance axon regeneration after optic nerve injury in vivo. Moreover, Nfe2l3 treatment provided a similar extent of neuroprotection and axon regeneration as viral vector-targeting of Pten and Klf9, which are prominent regulators of neuroprotection and long-distance axon regeneration. Finally, we bioinformatically characterized a gene network associated with Nfe2l3 in neurons, which revealed the association of Nfe2l3 with established mechanisms of neuroprotection and axon regeneration. Thus, Nfe2l3 is a novel neuroprotection and axon regeneration-promoting factor with a therapeutic potential for treating CNS injury and disease.

2024-02-22 | GSE253838 | GEO

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