Functionally linked potassium channel activity in cerebral endothelial and smooth muscle cells is compromised in Alzheimer’s disease

Abstract

The brain microcirculation is increasingly viewed as a potential target for disease-modifying drugs in the treatment of Alzheimer’s disease patients, reflecting a growing appreciation of evidence that cerebral blood flow is compromised in such patients. However, the pathogenic mechanisms in brain resistance arteries underlying blood flow defects have not yet been elucidated. Here we probed the roles of principal vasodilatory pathways in cerebral arteries using the APP23 mouse model of Alzheimer’s disease, in which amyloid precursor protein is increased approximately sevenfold, leading to neuritic plaques and cerebrovascular accumulation of amyloid-β similar to those in patients with Alzheimer’s disease. Pial arteries from APP23 mice (18 mo old) exhibited enhanced pressure-induced (myogenic) constriction because of a profound reduction in ryanodine receptor-mediated, local calcium-release events (“Ca 2+ sparks”) in arterial smooth muscle cells and a consequent decrease in the activity of large-conductance Ca 2+ -activated K + (BK) channels. The ability of the endothelial cell inward rectifier K + (Kir2.1) channel to cause dilation was also compromised. Acute application of amyloid-β 1-40 peptide to cerebral arteries from wild-type mice partially recapitulated the BK dysfunction seen in APP23 mice but had no effect on Kir2.1 function. If mirrored in human Alzheimer’s disease, these tandem defects in K + channel-mediated vasodilation could account for the clinical cerebrovascular presentation seen in patients: reduced blood flow and crippled functional hyperemia. These data direct future research toward approaches that reverse this dual vascular channel dysfunction, with the ultimate aim of restoring healthy cerebral blood flow and improving clinical outcomes.

KIR channel regulation of electrical conduction along cerebrovascular endothelium: Enhanced modulation during Alzheimer's disease

“…We examined K IR 2 channel activation using physiologically relevant increases in [K + ] E for vasodilation (up to 15 mmol/L). 38 Further, as compromised regulation of endothelial K IR 2 channels occurs in the brain during AD, [13][14][15][16] we pursued this work in aging 3xTg-AD mice. As consistent with previous findings, 7,10 we found that electrical conduction remains equally efficacious regardless of charge polarity (for hyperpolarization or depolarization) and axial direction.…”

“…Using a dual intracellular electrode method in endothelial tubes of mouse posterior cerebral arteries, 10 the current study addressed (1) bidirectional efficacy and (2) potential K IR 2 channel regulation of electrical conduction. Further, in light of recent data for the impact of Alzheimer's disease (AD) on overall vascular health, 11,12 and specifically on endothelial K IR 2 channels, [13][14][15][16] our study model of choice entailed young Pre-AD (1-3 months) and aged AD (13-18 months) 3xTg-AD animals. 17,18 With a normal reference of 5 mmol/L for extracellular potassium ([K + ] E ) 3,19,20 elevated [K + ] E as 8 to 15 mmol/L activated K IR 2 channels.…”

Theoretical investigations on a variable-coefficient generalized forced–perturbed Korteweg–de Vries–Burgers model for a dilated artery, blood vessel or circulatory system with experimental support

“…Nonlinear waves are physically and currently interesting [1][2][3]. Physical studies on the pulse waves in the human arteries have started from the ancient times until the present, while recent theoretical efforts have been focused on the probes for nonlinear pulse waves in the variable-radius arteries [4][5][6][7][8][9][10][11][12][13][14][15][16].…”

“…For simplicity, derivations are elided 8. The word 'quasi' implies that there still exist ρ 1 (t), ρ 2 (t) and ρ 3 (t), beyond the travelling-wave format.…”

William Bayliss and the enduring fascination of myogenic tone

“…hypertension, Osol & Halpern, 1985) or not (e.g. neurodegeneration, Taylor et al, 2022). The impetus for today's vascular physiologist is the promise of identifying additional myogenic control points that have the potential to restore normal blood flow in these conditions.…”