Role of Endothelial K+ Channels in Age-Related Dementia

Project Summary/Abstract
Cerebrovascular endothelial dysfunction impairs blood flow throughout the brain and is a causative factor of age-
related cognitive disorders such as Alzheimer’s disease (AD). Approximately 6.2 million Americans are living
with AD, whereby more than 95% of patients are over the age of 65; a demographic that will likely double by
2050. Cerebrovascular endothelium coordinates vasoreactivity of blood vessel networks for delivery of oxygen
and nutrients throughout brain tissue in accord with metabolic demand. Using a comprehensive, integrative and
longitudinal research approach, we endeavor to delineate and mechanistically clarify how endothelial dysfunction
precedes and accompanies progression of age-related dementia in the presence of ApoE Ɛ4 (Aim 1) and how
the advancement of AD pathology impacts cerebrovascular endothelial function towards endothelial dysfunction
(Aim 2). A central pathway for modulation of blood flow to and throughout the brain, but particularly in the
microcirculation, involves vasodilatory signaling pathways defined by the function of endothelial K+ channels
[Ca2+-activated (SKCa/IKCa; KCa2.3/KCa3.1) and inward-rectifying (KIR2.x) subtypes]. In particular, our recently
published data indicate that there are sex-independent reductions in cerebrovascular endothelial KIR2.x channel
function with both advancing age and AD pathology in mouse models. Further, our preliminary data demonstrate
that mild removal of membrane cholesterol using methyl β-cyclodextrin selectively restores KIR2.x (vs. SKCa/IKCa)
channel function to that of young, healthy conditions or better. Thus, we will test the central hypothesis that
impairment in endothelial KIR channel function caused by cellular cholesterol underlies cerebrovascular
aging and development of dementia. The Aims utilize an innovative integration of ex vivo (isolated cerebral
arteries/arterioles, freshly isolated endothelium), in vivo (cerebral perfusion, hyperemia, behavior), and
interventional (lipid regulation, cerebral endothelial KIR2.1 channel overexpression) approaches to
comprehensively test this hypothesis. The investigating research team includes experts in the biophysics of
endothelial function, vascular aging, cerebrovascular physiology/pathology, and cholesterol modulation of
endothelial K+ channels. Animal models entail aging endothelial cell-specific KIR2.1+/- & KIR2.1-/-, ApoE Ɛ2 / Ɛ3 /
Ɛ4 targeted replacement and 3xTg-AD vs. respective wild-type mice. In such manner, the Research Strategy
will be the first to delineate endothelial dysfunction, caused by changes in cellular cholesterol, as a causative
pathway of brain aging and AD while focusing on endothelial KIR2.x channels as a novel therapeutic target for
pharmacology and gene therapies. We will pursue fine-tuning of K+ channel activity spanning from molecular
approaches to the whole organism; reconciling molecular mechanisms with therapy. The ideal outcome is to find
and treat precise transitions between physiology and pathology uniting structural and functional vascular
“signatures” with behavioral alterations surrounding progressive phases of age- and AD-related dementia.

Grant Number: 5R01AG073230-04
NIH Institute/Center: NIH
Principal Investigator: Erik Behringer