Development of Alzheimer's Disease Progressively Alters Sex-Dependent KCa and Sex-Independent KIR Channel Function in Cerebrovascular Endothelium.

Abstract

Development of Alzheimer's disease (AD) pathology is associated with impaired blood flow delivery of oxygen and nutrients throughout the brain. Cerebrovascular endothelium regulates vasoreactivity of blood vessel networks for optimal cerebral blood flow. We tested the hypothesis that cerebrovascular endothelial Gq-protein-coupled receptor (GPCR; purinergic and muscarinic) and K+ channel [Ca2+-activated (KCa2.3/SK3 and KCa3.1/IK1) and inward-rectifying (KIR2.x)] function declines during progressive AD pathology. We applied simultaneous measurements of intracellular Ca2+ ([Ca2+]i) and membrane potential (Vm) in freshly isolated endothelium from posterior cerebral arteries of 3×Tg-AD mice [young, no pathology (1- 2 mo), cognitive impairment (CI; 4- 5 mo), extracellular Aβ plaques (Aβ; 6- 8 mo), and Aβ plaques + neurofibrillary tangles (AβT; 12- 15 mo)]. The coupling of ΔVm-to-Δ[Ca2+]i during AβT pathology was lowest for both sexes but, overall, ATP-induced purinergic receptor function was stable throughout AD pathology. SKCa/IKCa channel function itself was enhanced by ∼20% during AD (Aβ+ AβT) versus pre-AD (Young + CI) in males while steady in females. Accordingly, hyperpolarization-induced [Ca2+]i increases following SKCa/IKCa channel activation and Δ[Ca2+]i-to-ΔVm coupling was enhanced by ≥two-fold during AD pathology in males but not females. Further, KIR channel function decreased by ∼50% during AD conditions versus young regardless of sex. Finally, other than a ∼40% increase in females versus males during Aβ pathology, [Ca2+]i responses to the mitochondrial uncoupler FCCP were similar among AD versus pre-AD conditions. Altogether, AD pathology represents a condition of altered KCa and KIR channel function in cerebrovascular endothelium in a sex-dependent and sex-independent manner respectively.