Amyloid‐β Peptide‐mediated Disruption of Ca2+ dynamics in Contractile Pericytes

Abstract

Alzheimer's diseases and Cerebral amyloid angiopathy are diseases centered on the accumulation of toxic amyloid‐β‐containing plaques leading to the slow and progressive deterioration of the brain. Recent work has linked cardiovascular pathologies with these forms neurodegeneration, whereby vascular dysfunction potentiates the inability to efficiently clear toxic amyloid‐β from ageing brains. Our recent work describes how brain capillaries, the point of nutrient delivery and waste removal between circulating blood and surrounding neurons, and contractile pericytes act in concert to detect and respond to neural activity, increasing blood flow to meet local demand (functional hyperemia). Capillary pericytes closest to the terminal arteriole possess multiple vessel‐wrapping projections and are capable of exerting subcellular Ca2+‐dependent contraction. We tested the hypothesis that amyloid‐β peptides form Ca2+‐permeable pores within the plasma membrane of pericytes, leading to membrane permeabilization and pericyte Ca2+ dysregulation. Using transgenic mice expressing genetically encoded Ca2+ biosensors in contractile pericytes and smooth muscle cells, we found that free amyloid‐β oligomers (1–40) selectively increased the frequency of Ca2+ events in pericytes but not on neighboring arteriole smooth muscle cells. In addition, administration of amyloid‐β oligomers prevented the membrane depolarization‐induced contraction of pericytes by 60 mM KCl. These data suggest amyloid‐β peptide‐mediated increases in Ca2+ event frequency “short‐circuits” pericyte Ca2+ signaling, leading to Ca2+ overload and disruption of pericyte‐mediated control of junctional blood flow.Support or Funding InformationTotman Medical Research Trust, Foundation Leducq, Horizon 2020, NIH R01HL131181, R01HL121706, R37DK053832, and K01HL138215.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.