Enantiomeric Aβ peptides inhibit the fluid shear stress response of PIEZO1

Traumatic brain injury (TBI) elevates Abeta (A beta) peptides in the brain and cerebral spinal fluid. A beta peptides are amphipathic molecules that can modulate membrane mechanics. Because the mechanosensitive cation channel PIEZO1 is gated by membrane tension and curvature, it prompted us to test the effects of A beta on PIEZO1. Using precision fluid shear stress as a stimulus, we found that A beta monomers inhibit PIEZO1 at femtomolar to picomolar concentrations. The A beta oligomers proved much less potent. The effect of A beta s on Piezo gating did not involve peptide-protein interactions since the D and L enantiomers had similar effects. Incubating a fluorescent derivative of A beta and a fluorescently tagged PIEZO1, we showed that A beta can colocalize with PIEZO1, suggesting that they both had an affinity for particular regions of the bilayer. To better understand the PIEZO1 inhibitory effects of A beta, we examined their effect on wound healing. We observed that over-expression of PIEZO1 in HEK293 cells increased cell migration velocity similar to 10-fold, and both enantiomeric A beta peptides and GsMTx4 independently inhibited migration, demonstrating involvement of PIEZO1 in cell motility. As part of the motility study we examined the correlation of PIEZO1 function with tension in the cytoskeleton using a genetically encoded fluorescent stress probe. A beta peptides increased resting stress in F-actin, and is correlated with A beta block of PIEZO1-mediated Ca2+ influx. A beta inhibition of PIEZO1 in the absence of stereospecific peptide-protein interactions shows that A beta peptides modulate both cell membrane and cytoskeletal mechanics to control PIEZO1-triggered Ca2+ influx.