Impaired KATP channel‐mediated electro‐metabolic signaling in capillary pericytes disrupts brain blood flow control in aging and Alzheimer’s disease

Abstract

AbstractBackgroundAging is associated with a gradual decrease in cerebral blood flow and disruptions in neurovascular coupling, causing a mismatch of energy supply and demand that can precipitate neuronal dysfunction and cognitive decline. We have recently discovered that ATP‐sensitive K+ (KATP) channels in capillary thin‐strand pericytes act as metabolic sentinels that couple subtle changes in local glucose to electrical signals such that blood flow is rapidly adjusted in response to decreased availability of this critical energy substrate. Aging and Alzheimer’s disease (AD) are linked to an increase in caveolin, association with which can disrupt the ability of KATP channels to sense intracellular energy state by decreasing sensitivity to ADP. Here, we demonstrate than an interaction between caveolin and KATP channels in aging animals underlies the loss of electro‐metabolic blood flow control by brain pericyte KATP channels.MethodUsing a combination of advanced techniques such as in vivo two‐photon laser scanning microscopy to image hemodynamics, and electrophysiological recordings from isolated cortical thin‐strand pericytes, we determine the effect of aging and familial AD on brain blood flow control by pericyte KATP channels in young (2‐3 months old) and aged (12‐14 months old) 5xFAD mice. We investigate the interaction between caveolin and KATP channels, and whether disrupting caveolae can restore the energy sensing abilities of pericyte KATP channels in older mice.ResultIn young mice, inhibiting glucose import into the brain with a glucose transporter‐1 blocker (1 µM BAY‐876) activates pericyte KATP channels to dilate arterioles and capillaries, and increase blood flow. Remarkably, this effect is completely lost in older mice. Our data reveal a key interaction between caveolin and KATP channels underlies this dysfunction, and disrupting caveolae in older mice reinstates the ability of pericyte KATP channels to sense decreases in local glucose.ConclusionThin‐strand pericytes protect neuronal health by coupling local energy substrate availability with hyperemia, and the disruption of this mechanism can contribute to the development of blood flow dysregulation observed in dementia. Our data unveil a role of caveolin in the loss of energy sensing by pericyte KATP channels, which can be leveraged to augment blood flow in aging individuals.