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Androgen alleviates neurotoxicity of ?-amyloid peptide (A?) by promoting microglial clearance of A? and inhibiting microglial inflammatory response to A?.

ABSTRACT: AIMS:Lower androgen level in elderly men is a risk factor of Alzheimer's disease (AD). It has been reported that androgen reduces amyloid peptides (A?) production and increases A? degradation by neurons. Activated microglia are involved in AD by either clearing A? deposits through uptake of A? or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on A? uptake and clearance and A?-induced inflammatory response in microglia, on neuronal death induced by A?-activated microglia, and explored underlying mechanisms. METHODS:Intracellular and extracellular A? were examined by immunofluorescence staining and Western blot. Amyloid peptides (A?) receptors, A? degrading enzymes, and pro-inflammatory cytokines were detected by RT-PCR, real-time PCR, and ELISA. Phosphorylation of MAP kinases and NF-?B was examined by Western blot. RESULTS:We found that physiological concentrations of androgen enhanced A?42 uptake and clearance, suppressed A?42 -induced IL-1? and TNF? expression by murine microglia cell line N9 and primary microglia, and alleviated neuronal death induced by A?42 -activated microglia. Androgen administration also reduced A?42 -induced IL-1? expression and neuronal death in murine hippocampus. Mechanistic studies revealed that androgen promoted microglia to phagocytose and degrade A?42 through upregulating formyl peptide receptor 2 and endothelin-converting enzyme 1c expression, and inhibited A?42 -induced pro-inflammatory cytokines expression via suppressing MAPK p38 and NF-?B activation by A?42 , in an androgen receptor independent manner. CONCLUSION:Our study demonstrates that androgen promotes microglia to phagocytose and clear A?42 and inhibits A?42 -induced inflammatory response, which may play an important role in reducing the neurotoxicity of A?.

SUBMITTER: Yao PL

PROVIDER: S-EPMC6492702 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Androgen alleviates neurotoxicity of β-amyloid peptide (Aβ) by promoting microglial clearance of Aβ and inhibiting microglial inflammatory response to Aβ.

Yao Peng-Le PL Zhuo Shu S Mei Hong H Chen Xiao-Fang XF Li Na N Zhu Teng-Fei TF Chen Shi-Ting ST Wang Ji-Ming JM Hou Rui-Xing RX Le Ying-Ying YY

CNS neuroscience & therapeutics 20170920 11

<h4>Aims</h4>Lower androgen level in elderly men is a risk factor of Alzheimer's disease (AD). It has been reported that androgen reduces amyloid peptides (Aβ) production and increases Aβ degradation by neurons. Activated microglia are involved in AD by either clearing Aβ deposits through uptake of Aβ or releasing cytotoxic substances and pro-inflammatory cytokines. Here, we investigated the effect of androgen on Aβ uptake and clearance and Aβ-induced inflammatory response in microglia, on neuro ...[more]

PMID: 28941188

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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.

Project description:Background: Extracellular vesicles, including exosomes, are secreted by a variety of cell types in the central nervous system. Exosomes play a role in removing intracellular materials from the endosomal system. Alzheimer's disease (AD) is caused by an overproduction or reduced amyloid-beta (Aβ) peptide clearance. Increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway. Therapeutic ultrasound stimulation demonstrated its potential for promoting Aβ degradation efficiency in clinical trials. However, the underlying mechanism of ultrasound stimulation is still unclear. Methods: In this study, astrocytes, the most abundant glial cells in the brain, were used for exosome production. Post insonation, exosomes from ultrasound-stimulated HA cells (US-HA-Exo) were collected, nanoparticle tracking analysis and protein analysis were used to measure and characterize exosomes. Neuroprotective effect of US-HA-Exo in oligomeric Aβ42 toxicated SH-SY5Y cells was tested. Cellular uptake and distribution of exosomes were observed by flow cytometry and confocal laser scanning microscopy. Focused ultrasound (FUS) with microbubbles was employed for blood-brain-barrier opening to achieve brain-targeted exosome delivery. After US-HA-Exo/FUS treatment, amyloid-β plaque in APP/PS1 mice were evaluated by Aβ immunostaining and thioflavin-S staining. Results: We showed that ultrasound resulted in an almost 5-fold increase in the exosome release from human astrocytes. Exosomes were rapidly internalized in SH-SY5Y cells, and colocalized with FITC-Aβ42, causing a decreased uptake of FITC-Aβ42. CCk-8 test results showed that US-HA-Exo could mitigate Aβ toxicity to neurons in vitro. The therapeutic potential of US-HA-Exo/FUS delivery was demonstrated by a decrease in thioflavin-S-positive amyloid plaques and Aβ immuno-staining, a therapeutic target for AD in APP/PS1 transgenic mice. The iTRAQ-based proteomic quantification was performed to gain mechanistic insight into the ultrasound effect on astrocyte-derived exosomes and their ability to alleviate Aβ neurotoxicity. Conclusion: Our results imply that US-HA-Exo have the potential to provide neuroprotective effects to reverse oligomeric amyloid-β-induced cytotoxicity in vitro and, when combined with FUS-induced BBB opening, enable the clearance of amyloid-β plaques in vivo.

Dataset Information

Androgen alleviates neurotoxicity of ?-amyloid peptide (A?) by promoting microglial clearance of A? and inhibiting microglial inflammatory response to A?.

Publications

Androgen alleviates neurotoxicity of β-amyloid peptide (Aβ) by promoting microglial clearance of Aβ and inhibiting microglial inflammatory response to Aβ.

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