Alzheimer’s disease as a condition of accelerated aging of cerebrovascular endothelial function

Abstract

Currently ~5.8 million Americans have Alzheimer’s disease (AD), whereby >95% of patients are ≥65 years old. Age‐related cognitive disorders including AD are associated with impaired blood flow delivery of oxygen and nutrients throughout the brain. Cerebrovascular endothelium is central to coordinating vasoreactivity of blood vessel networks for optimal cerebral blood flow. Thus we tested the hypothesis that cerebrovascular endothelial Gq‐protein‐coupled receptor (GPCR; P2Y) and K+ channel (KCa2.3/SK3 & KCa3.1/IK1, KIR2.1) function declines during progressive age and AD pathology. Using Fura‐2 photometry (intracellular Ca2+) and sharp electrodes (membrane potential), we measured the function of endothelial tubes of posterior cerebral arteries of male and female mice (n≥5/group): C57BL/6 [young (4–6 mo), middle‐aged (12–16 mo), and old (24–28 mo)] & 3xTgAD [young, no pathology (1–2 mo), mild cognitive impairment (MCI; 4–5 mo), extracellular Aβ plaques (Aβ; 6–8 mo), and Aβ plaques + neurofibrillary tangles (AβT; 12–15 mo)]. During normal aging, P2Y function in response to ATP (100 μM) was reduced in male vs. females during old age. In contrast, SKCa/IKCa channel function in response to NS309 (0.3–1 μM) decreased in old females vs. young females & old males. Activation of KIR channels to elevated extracellular K+ (15 mM KCl) decreased with advancing age regardless of sex. For 3xTgAD animals, P2Y function was maintained throughout AD pathology in females but decreased during AβT in males. SKCa/IKCa channel function was reduced in Aβ females vs. Aβ males. Further, KIR function decreased during Aβ and AβT groups regardless of sex. Altogether, AD pathology accelerates the impact of advancing age on cerebrovascular endothelium by at least 12 mo while indicating a sex‐based contrast in declined function of GPCRs and K+ channels across males and females respectively. Modulation of endothelial K+ channel activity may optimize cerebral blood flow during aging and AD to prevent and treat neurodegenerative disease.Support or Funding InformationThis research was supported by National Institutes of Health grants R00AG047198 & R56AG062169 (EJB).