Amyloid beta Aβ_1-40 activates Piezo1 channels in brain capillary endothelial cells

Amyloid-beta (Aβ) peptide accumulation on blood vessels in the brain is a hallmark of neurodegeneration. While Aβ peptides constrict cerebral arteries and arterioles, their impact on capillaries is less understood. Aβ was recently shown to constrict brain capillaries through pericyte contraction, but whether-and if so how-Aβ affects endothelial cells (ECs) remains unknown. ECs represent the predominant vascular cell type in the cerebral circulation, and we recently showed that the mechanosensitive ion channel Piezo1 is functionally expressed in the plasma membrane of ECs. Since Aβ disrupts membrane structures, we hypothesized that Aβ_1-40, the predominantly deposited isoform in the cerebral circulation, alters endothelial Piezo1 function. Using patch clamp electrophysiology and freshly isolated capillary ECs, we assessed the impact of Aβ_1-40 peptide on single-channel Piezo1 activity. We show that Aβ_1-40 increased Piezo1 open probability and the channel open time. Aβ_1-40 effects were absent when Piezo1 was genetically deleted or when a superoxide dismutase/catalase mimetic was used. Further, Aβ_1-40 enhanced Piezo1 mechanosensitivity and lowered the pressure of half-maximal Piezo1 activation. Our data collectively suggest that Aβ_1-40 facilitates higher Piezo1-mediated cation influx in brain ECs. These novel findings have the potential to unravel the possible involvement of Piezo1 modulation in the pathophysiology of neurodegenerative diseases characterized by Aβ accumulation.