LAUSR

Alzheimer’s disease (AD), the most common form of dementia, affects over 6 million Americans and has devastating emotional and physical consequences for both the patient and surrounding loved ones. Current drug therapies are principally targeted at the main disease-causing peptide in AD, amyloid-beta (Aβ). These drugs reduce symptoms at the onset of the disease but have negligible positive impacts once AD has progressed. Thus, new avenues for therapeutic intervention are imperative. It is currently understood that reduced cerebral blood flow (CBF), due to an increased constriction of cerebral blood vessels, contributes to the pathogenesis of AD. Calcium (Ca2+) influx through voltage-gated L-type calcium CaV1.2 channels is essential for vascular smooth muscle (VSM) contractility, arterial diameter, and CBF. Yet, how Aβ affects CaV1.2 channel activity and vascular function is unclear. Here, we test the hypothesis that Aβ promotes vascular CaV1.2 clustering leading to increased CaV1.2 channel activity and enhanced vascular reactivity. The hypothesis was tested using a multi-scale approach that includes super-resolution microscopy, patch-clamp electrophysiology, and pressure myography using freshly isolated cerebral VSM and arteries from WT mice. Initial experiments found that exposing VSM to 100 nM Aβ for 10 minutes stimulates the redistribution of CaV1.2 into superclusters. This observation was correlated with an increase in CaV1.2 channel activity and the frequency and strength of cooperative events, which are expected to amplify Ca2+ influx and alter vascular contractility. Consistent with this premise, pressurized cerebral arteries exposed to Aβ showed an elevation in myogenic tone. These results suggest that Aβ impacts vascular CaV1.2 spatiotemporal properties to control vascular contractility. Moreover, results may provide new mechanistic insight into a link between impaired CaV1.2 function, VSM dysfunction and AD. NIH R01HL149127 and R01HL149127S1(to MFN). This is the full abstract presented at the American Physiology Summit 2023 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.