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The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to A? Plaques.

ABSTRACT: Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female AppNL-G-F mice over time demonstrate that progressive amyloid-? accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alzheimer's disease (AD) risk genes. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.

SUBMITTER: Sala Frigerio C

PROVIDER: S-EPMC7340153 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques.

Sala Frigerio Carlo C Wolfs Leen L Fattorelli Nicola N Thrupp Nicola N Voytyuk Iryna I Schmidt Inga I Mancuso Renzo R Chen Wei-Ting WT Woodbury Maya E ME Srivastava Gyan G Möller Thomas T Hudry Eloise E Das Sudeshna S Saido Takaomi T Karran Eric E Hyman Bradley B Perry V Hugh VH Fiers Mark M De Strooper Bart B

Cell reports 20190401 4

Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female App<sup>NL-G-F</sup> mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alz ...[more]

PMID: 31018141

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Project description:Alzheimer's disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aβ. In particular, RAGE-TXNIP axis is required for targeting Aβ in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aβ transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aβ toxicity. Furthermore, Aβ shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1β and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE-TXNIP axis inhibits Aβ-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aβ to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1β and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.

Dataset Information

The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to A? Plaques.

Publications

The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques.

Similar Datasets

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