Piezo1 Activation Promotes Glial Anti-inflammation and Tau Dephosphorylation in an Alzheimer’s Disease Model

Piezo1 is a mechanosensitive ion channel that has been recently recognized to mitigate Alzheimer’s disease pathological signatures such as beta-amyloid (Aβ) deposition and microglial proinflammation. However, much less is known on how Piezo1 regulates tauopathy, partly due to lack of Alzheimer’s disease (AD) model to elucidate the complex neuroglia interactions. Here, we report how the activation of Piezo1 triggers an anti-inflammatory response and reduces tauopathy using our human Alzheimer’s disease model. We first observed that the activation of Piezo1 suppressed microglial nuclear factor-kB (NFκB), while promoting Aβ clearance and reducing oxidative stress. Piezo1 also reduced astrocytic proinflammation driven by Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), while promoting Aβ clearance and reducing oxidative stress. We discovered that Piezo1 facilitated tau dephosphorylation and reduced tau hyperphosphorylation by independently enhancing protein phosphatase 2A (PP2A) and inhibiting cyclin-dependent kinase 5 (CDK5) in neurons. Our human AD model demonstrated that Piezo1 served as a crucial mechanosensor in alleviating tauopathy and glial proinflammation, providing a potential therapeutic target in tauopathy-mediated neurodegeneration for regenerative medicine.