Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease

The brain is the softest organ in the body, and any change in the mechanical properties of the tissue induces the activation of glial cells, astrocytes and microglia. Amyloid plaques, one of the main pathological features of Alzheimer's disease (AD), are substantially harder than the surrounding brain tissue and can activate astrocytes and microglia resulting in the glial engulfment of plaques. Durotaxis, a migratory preference towards stiffer tissue, is prompting microglia to form a mechanical barrier around plaques reducing amyloid β (Aβ) induced neurotoxicity. Mechanoreceptors are highly expressed in the brain, particularly in microglia. The large increase in the expression of the mechanoreceptor Piezo1 was observed in the brains from AD animal models and AD patients in plaque encompassing glia. Importantly, Piezo1 function is regulated via force-from-lipids through the lipid composition of the membrane and membranous incorporation of polyunsaturated fatty acids (PUFAs) can affect the function of Piezo1 altering mechanosensitive properties of the cell. On the other hand, PUFAs dietary supplementation can alter microglial polarization, the envelopment of amyloid plaques, and immune response and Piezo1 activity was implicated in the similar modulations of microglia behavior. Finally, PUFAs treatment is currently in use in medical trials as the therapy for sickle cell anemia, a disease linked with the mutations in Piezo1. Further studies are needed to elucidate the connection between PUFAs, Piezo1 expression, and microglia behavior in the AD brain. These findings could open new possibilities in harnessing microglia in AD and in developing novel therapeutic strategies.