Early disruptions in brain capillary blood flow control in a mouse model of Alzheimer's disease.

In Alzheimer's disease (AD), vascular dysfunction and impaired control of brain blood flow can disrupt cellular bioenergetics decades before cognitive decline. Identifying the earliest vascular changes is therefore critical for developing therapies that intervene before the cascading events leading to neuronal decline. Brain energy supply is dynamically controlled by the cerebral vasculature, where capillary thin-strand pericytes are emerging as key players. We recently identified a central role for ATP-sensitive potassium (K+, KATP) channels in enabling thin-strand pericytes to sense local neuronal activity and generate hyperpolarizing signals that are transmitted via capillary endothelial cells to upstream arterioles, eliciting increases in blood flow. Importantly, thin-strand pericyte KATP channels are the centerpiece of an electro-metabolic "energy switch" mechanism that couples decreases in local glucose to hyperemia, providing a failsafe to ensure continual energy substrate supply to support neuronal function. Disruption of this mechanism could therefore precipitate an imbalance between demand and supply, creating an energy gap for neurons that leads to deleterious consequences. We demonstrate that capillary control of blood flow is disrupted in the early stages of disease progression in mice expressing familial AD mutations (5xFAD). Transgenic 5xFAD mice exhibit early disruption of capillary signaling, beginning with dysfunctional endothelial inward rectifier K+ (Kir)2.1 channels at 2-4 mo, disabling transmission of KATP-mediated signals to upstream blood flow control machinery, followed by direct impairment of pericyte KATP channel function by 6-8 mo. Together, these deficits cause early and sustained failure of electrical signaling from deep capillary pericytes to upstream arterioles and arteriole-capillary transition (ACT) zone vessels, limiting KATP-dependent energy-switch-mediated blood flow control. Our findings define a temporal and mechanistic framework linking familial AD mutations to early capillary signaling dysfunction and highlight preservation of capillary blood flow control as a potential therapeutic target to protect against downstream effects of amyloid β accumulation.