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Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.

ABSTRACT: Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Abeta-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Abeta-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1beta (interleukin-1beta) and tumor necrosis factor alpha (TNFalpha), suggesting that there is an inverse correlation between cytokine production and Abeta clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFalpha decreased the expression of SRA and CD36 and reduced Abeta uptake. Our data indicate that, although early microglial recruitment promotes Abeta clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Abeta deposition downregulate genes involved in Abeta clearance and promote Abeta accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.

SUBMITTER: Hickman SE

PROVIDER: S-EPMC2597474 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.

Hickman Suzanne E SE Allison Elizabeth K EK El Khoury Joseph J

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080801 33

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of beta-amyloid (Abeta) before formation of senile plaques. However, persistent Abeta accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Abeta may decrease with age and progression of AD pathology. To determine the effects of aging and Abeta deposition on microglial ability to clear Abeta, we used quantitative PCR to analyze gene expression i ...[more]

PMID: 18701698

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Project description:BackgroundMicroglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimer's disease (AD), toxic amyloid beta (Aβ) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of Aβ. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia had been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored.MethodsHere we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and Aβ pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations.ResultsWe show that PIEZO1 orchestrates Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. Aβ inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in Aβ clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single-cell datasets.ConclusionThese results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated Aβ burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD.

Dataset Information

Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.

Publications

Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice.

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