Enantiomeric Aβ Peptides Inhibit the Fluid Shear Stress Response of PIEZO1

Abstract

Using precision fluid shear stress as a stimulus on a cell line overexpressing PIEZO1, we show that Aβ peptide monomers inhibit PIEZO1 at fM to pM concentrations. The Aβ aggregates were much less potent. The effect of Aβs on PIEZO gating did not involve peptide-protein interactions since the D and L enantiomers had similar effects. Aβ peptides co-localized with PIEZO1 as seen with a fluorescent derivative of Aβ and a fluorescently tagged PIEZO1. To better understand the inhibitory effects of Aβ, we examined the effects in a wound healing assay. Simply over-expression of PIEZO1 in HEK293 cells increased cell migration velocity ∼10-fold, and both enantiomeric Aβ peptides and GsMTx4 inhibited migration. We examined the correlation of PIEZO1 function with the tension in F-actin using a genetically encoded fluorescent stress probe. Aβ peptides increased resting stress in F-actin, correlated with the Aβ block of PIEZO1-mediated Ca2+ influx. Aβ inhibition of PIEZO1 in the absence of stereospecific peptide-protein interactions shows that Aβ peptides modulate both cell membrane and cytoskeletal mechanics to control PIEZO1-triggered Ca2+ influx.