Microglial amyloid beta clearance is driven by PIEZO1 channels.

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Microglia are brain immune cells crucial for homeostasis, sensing pathology and eliminating threats.
• In Alzheimer's disease (AD), impaired amyloid beta (Aβ) clearance by microglia contributes to plaque accumulation, particularly in late-onset AD.
• While neurochemical pathways regulating microglia are studied, their mechanical receptors remain largely unexplored.

Purpose of the Study:

• To investigate the role of the mechanotransduction ion channel PIEZO1 in microglial function related to Alzheimer's disease.
• To determine if activating PIEZO1 can enhance microglial Aβ clearance and improve AD-related pathology.

Main Methods:

• Investigated PIEZO1 expression and function in human and mouse microglia.
• Utilized Yoda1, a PIEZO1 agonist, on human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGL) to assess cell survival, metabolism, phagocytosis, and lysosomal activity.
• Administered Yoda1 to 5xFAD mice to evaluate in vivo effects on microglial Iba1 expression and Aβ pathology.
• Analyzed PIEZO1 gene expression in human and mouse AD datasets.

Main Results:

• PIEZO1 is expressed and functional in microglia, orchestrating Aβ clearance by enhancing microglial survival, phagocytosis, and lysosomal activity.
• Yoda1 activation of PIEZO1 improved microglial phagocytosis and Aβ clearance in both human and mouse AD models.
• PIEZO1 expression correlated with a distinct microglial transcriptional phenotype in AD, impacting cellular metabolism.

Conclusions:

• Compromised microglial function in AD can be improved by activating PIEZO1 channels, leading to reduced Aβ burden.
• Pharmacological targeting of PIEZO1 mechanoreceptors in microglia presents a novel therapeutic avenue for Alzheimer's disease.