Objective: Endothelial cell (EC) coupling occurs through gap junctions and underlies cerebral blood flow regulation governed by inward-rectifying K+ (KIR ) channels. This study addressed effects of KIR channel activity on EC coupling before and during Alzheimer's disease (AD).
Methods: Intact EC tubes (width: ~90-100 μm; length: ~0.5 mm) were freshly isolated from posterior cerebral arteries of young Pre-AD (1-3 months) and aged AD (13-18 months) male and female 3xTg-AD mice. Dual intracellular microelectrodes applied simultaneous current injections (±0.5-3 nA) and membrane potential (Vm ) recordings in ECs at distance ~400 μm. Elevated extracellular potassium ([K+ ]E ; 8-15 mmol/L; reference, 5 mmol/L) activated KIR channels.
Results: Conducted Vm (∆Vm ) responses ranged from ~-30 to 30 mV in response to -3 to +3 nA (linear regression, R2 ≥ .99) while lacking rectification for charge polarity or axial direction of spread. Conduction slope decreased ~10%-20% during 15 mmol/L [K+ ]E in Pre-AD males and AD females. 15 mmol/L [K+ ]E decreased conduction by ~10%-20% at lower ∆Vm thresholds in AD animals (~±20 mV) versus Pre-AD (~±25 mV). AD increased conducted hyperpolarization by ~10%-15% during 8-12 mmol/L [K+ ]E .
Conclusions: Brain endothelial KIR channel activity modulates bidirectional spread of vasoreactive signals with enhanced regulation of EC coupling during AD pathology.
Keywords: Alzheimer's disease; Brain endothelium; K+ ion channels; electrical conduction; endothelial cell coupling.
© 2022 John Wiley & Sons Ltd.