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bioRxiv · 10.1101/2022.03.23.485446

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer's disease

Hu, J.·Zhu, H.·Yang, Q.·Shen, H.·Chai, G.·Zhang, B.·Chen, S.·Chen, Q.·Cai, Z.·Li, H.·Hou, L.·Mo, W.
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Abstract

The pathology of Alzheimers disease (AD) is associated with the extracellular amyloid-{beta} (A{beta}) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of A{beta} fibrils. The upregulation of Piezo1 in A{beta} plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of A{beta} plaques, resulting in the exacerbation of A{beta} and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain A{beta} burden and cognitive impairment in the 5xFAD mouse. Together, our results reveal Piezo1, as a mechanosensor of A{beta} fibrils stiffness in microglia, could represent a promising therapeutic target for AD.

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Hu, J., Zhu, H., Yang, Q., Shen, H., Chai, G., Zhang, B., Chen, S., Chen, Q., Cai, Z., Li, H., Hou, L., Mo, W.. 2022-03-25. Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer's disease. https://doi.org/10.1101/2022.03.23.485446

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