Electrical Imbalance Impairs Pericyte Metabolic Sensing and Blood Flow Control in Alzheimer's Disease

Disruptions to the mechanisms governing the metabolic supply-and-demand relationship that are integral to brain energy homeostasis can have deleterious consequences on brain health, making it vulnerable to the development of age-related disorders such as Alzheimer's disease (AD). Energy supply is dynamically and precisely controlled by mechanisms inherent to the cerebral vasculature, and here, capillary thin-strand pericytes are emerging as key players. We have found that a K ATP channel signaling complex imbues pericytes with the ability to detect subtle changes in local glucose, and rapidly couples decreases in this key energy substrate to robust increases in blood flow. We hypothesize that this pericyte electro-metabolic signaling is disrupted in AD, leading to blood flow disturbances which may severely impact neuronal health and function if left unchecked. Using a combination of in vivo imaging and ex vivo single-cell electrophysiology in young (2-4 months) and mature (6-8 months) mice with familial AD mutations (5xFAD), we show that pericyte K ATP channel activity and glucose sensing is significantly impaired in transgenic (Tg) 5xFAD compared to wildtype (Wt) littermates. Our data demonstrate that a possible mechanism for this disruption is an interaction between K ATP channels and calcium-activated chloride channels (CaCC) in thin-strand pericytes. In healthy mice, vasodilatory K ATP channels and vasoconstrictive CaCCs work in tandem to finely control pericyte electrical activity and maintain blood flow at optimum levels. However, in Tg 5xFAD mice, a tip in this electrical balance in favor of CaCCs impedes pericyte K ATP channel activation and blocking CaCCs restores pericyte K ATP channel metabolic sensing and its control over blood flow. Therefore, this study lends novel insights on the mechanisms underlying loss of blood flow control by thin-strand pericytes in AD which may be leveraged to develop future therapies directing at correcting cerebral blood flow deficits and preserving cognitive health. 1DP2OD02944801 (TL), 1R01AG066645 (TL), 5R01NS115401 (TL), 1R01NS138179 (TL), and 830093 (AH) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.