Restoring capillary-to-arteriole signaling in Alzheimer's Disease

There is growing evidence for vascular contributions to cognitive impairments in Alzheimer’s Disease (AD). Functional hyperemia, which refers to local increases in blood flow in response to local increases in brain activity, is impaired early in patients and animal models of AD. The mechanisms underlying functional hyperemia are referred to as neurovascular coupling (NVC). A key player in NVC is the inward rectifying K+ channel (Kir2.1) in capillary endothelial cells (cECs). Activation of Kir2.1 channels initiates a retrograde hyperpolarizing signal which causes upstream arterioles to dilate and increase local blood flow. Studies have shown that Kir2.1 channel function is impaired in the 5xFAD mouse model for AD, and administration of Kir2.1 cofactor, phosphatidylinositol 4,5-bisphosphate (PIP2), was suffcient to restore channel function and functional hyperemia deficits. The objective of this study is to characterize the effect of AD on NVC. Since AD is characterized by the deposition of amyloid beta (Aβ), we hypothesize that Aβ is impairing Kir2.1 function in cECs at an early stage of the disease. Using 6-month-old female and male 5xFAD mice, we performed our ex vivo capillary-parenchymal arteriole (CaPA) technique to investigate NVC responses by directly stimulating capillaries and recording upstream arteriolar dilation in real time. We further tested the direct effect of Aβ oligomers (200 nM) and reactive oxygen species (ROS) scavengers (superoxide dismutase 120 U/mL + catalase 1000 U/mL), to probe their effect on the NVC response. Finally, to test the ability of PIP2 to rescue the NVC response, systemic administration via intraperitoneal injection was performed one hour before CaPA experiment. Consistent with a NVC impairment in AD, capillary stimulation with 10 mM K+ failed to evoke upstream arteriolar dilation in 5xFAD mice at an early stage, and this impairment was recapitulated in wild type mice after treatment with Aβ. Importantly, Aβ only caused a modest arteriole constriction (20.11% ± 5.24 %) but did not impair its ability to dilate in response to direct stimulation with 10 mM K+, suggesting an effect on cECs. ROS scavenging during Aβ treatment prevented NVC impairment as 10 mM K+ capillary stimulation induced an upstream arteriolar dilation of 59% of max dilation. Finally, systemic administration of PIP2 also rescued the NVC response to the levels observed in control conditions. Taken together, our results suggest that Aβ is causing impairment in NVC via increasing ROS production, specifically at the capillary endothelial level. This increase in ROS is likely leading to PIP2 degradation and causing Kir2.1 channel dysfunction. Administration of PIP2 was suffcient to rescue the NVC response, suggesting a possible strategy for rescuing functional hyperemia in AD. This study was supported by a research grant from the Center for Women’s Health Research located at the University of Colorado Anschutz Medical Campus; 2 research grants from the University of Pennsylvania Orphan Disease Center in partnership with the cureCADASIL (2019 and 2022), the National Institute of Neurological Disorders and Stroke RF1/R01NS129022, and the National Heart, Lung, and Blood Institute R01HL136636 to FD. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.