Alteration of Calcium and Electrical Dynamics in Cerebrovascular Endothelium During Development of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia characterized by a decline in cognitive function among the elderly. Currently, ~5.7 million Americans are living with AD and this number will increase to ~14 million by 2050. Age‐related AD alters blood flow to the brain and is associated with cerebral hypoperfusion, due in part, to impaired vascular endothelial function. However, it is unknown whether AD pathology impacts the biophysical functions of key cerebral vascular G‐protein‐coupled receptors (GPCRs) and K+ channels (KCa2.3 or SKCa, KCa3.1 or IKCa) that govern blood flow via an electrical vasodilatory pathway known as endothelium‐derived hyperpolarization (EDH). Thus, we tested the hypothesis that cerebrovascular endothelial purinergic receptors and Ca2+‐activated K+ channels become functionally dysregulated during progression of AD. We used the triple mutation mouse model of AD (3xTgAD) to examine endothelium isolated from posterior cerebral arteries in young control (YC; 1–2 mo), amyloid‐β plaques (Aβ; 6–8 mo), and plaques + neurofibrillary tangles (Aβ+Tau; ≥ 12 mo); n ≥ 3 male & n ≥ 3 female mice/group. Intracellular calcium concentration ([Ca2+]i) and membrane potential (Vm) were simultaneously measured using Fura‐2 photometry and sharp electrodes (pH 7.4, 37°C). EDH was demonstrated by an increase in [Ca2+]i (ΔF340/F380 ≥ 0.3) concomitant with ΔVm ≥ −10 mV in response to the P2Y agonist ATP (100 μM, 3 min). Membrane hyperpolarization to ATP during Aβ+Tau vs. YC decreased (ΔVm, mV; YC: −20±4, Aβ: −17±2, Aβ+Tau: −13±3) while [Ca2+]i responses were maintained. In contrast, hyperpolarization increased during Aβ and Aβ+Tau (ΔVm, mV; YC: −29±3, Aβ: −36±2, Aβ+Tau: −38±3) during direct activation of SKCa/IKCa alone with SKA‐31 (10 μM, 5 min). Finally, Δ[Ca2+]i and ΔVm responses to hydrogen peroxide (H2O2; 200 μM, 20 min) in young control animals were greater by > 40% as compared to Aβ & Aβ+Tau. These data suggest coupling of endothelial SKCa/IKCa function with Ca2+ signaling is reduced and adaptation to oxidative stress occurs during the development of AD. Altogether, endothelial K+ channel function may be directly calibrated for optimal cerebral blood flow to maintain a healthy brain with aging while helping to prevent neurodegenerative disease.Support or Funding InformationThis research is supported by Loma Linda University School of Medicine new faculty start‐up funds and National Institutes of Health grants R00AG047198 & R56AG062169 (EJB).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.