Alzheimer's Disease, Piezo2 Channelopathy, Piezo1 Channelopathy, and the Body-Wide Piezo2 System.

Alzheimer's disease initiates pathophysiology in the 10 to 20 years prior to detectable clinical symptoms. A recent genetic analysis implicated the critical role of Piezo2 in Alzheimer's disease pathophysiology. A recent genetic study, involving PIEZO1 manipulation, showed that phosphatidylinositol 4,5-bisphosphate (PIP2) rectified brain capillary endothelial Piezo1 channelopathy in a mouse model of Alzheimer's disease. However, the present opinion paper posits that the initiating microdamage is in the prefrontal cortex, further upstream of pathophysiology, namely an irreversible Piezo2 channelopathy of glutamatergic terminals that is proposed to finely regulate oxytocin release resulting from stressful ultradian events, leading to impaired ultradian rhythm. The involvement of Piezo2 in the defensive arousal response reveals an underlying body-wide Piezo2 system of which the proposed prefrontal Piezo2 channelopathy is possibly a critical locus. PIP2 is emerging as a potential treatment method for Piezo channelopathy in Alzheimer's disease. However, the challenge of its more precise administration to target affected regions of the brain still remains.