Abstract 10470: Endothelial Dysfunction in Leptomeningeal and Peripheral Arterioles Induced by ß-amyloid Peptides: A Novel Human Model to Study Alzheimer’s Disease
Background: Treatments effective in transgenic mice have so far failed in human clinical trials to treat Alzheimer’s disease (AD), likely due to deficient recapitulation of human condition by existing mouse models and the need to intervene early. Vascular dysfunction occurs early in AD and the mechanisms linking it to AD pathogenesis remain poorly understood. We tested the hypothesis that beta amyloid peptides (Aβ) induce endothelial dysfunction through reduced nitric oxide (NO) biovailability and that the effects will be similar in brain (leptomeningeal) and peripheral (abdominal adipose) human arterioles.
Methods: In 7 cadavers (82±2.5 years) that underwent rapid autopsy (postmortem interval 2.6±0.2 hours), 6 had leptomeningeal arterioles that remained vasoreactive. Leptomeningeal arterioles were cannulated, pressurized and dilator responses to acetylcholine (10-8-10-4M) and papaverine (10-4M) were tested at baseline and following 1-hour exposure to Aβ42 (2 μM in 4, 1 μM in 1). Abdominal adipose arterioles in 3 of the cadavers as well as in 10 living subjects (without AD, undergoing routine hernia surgery) were also tested. Human umbilical vein endothelial cells (HUVECs) were exposed to 24 hours of vehicle, Aβ42 (2 μM) or scrambled Aβ42 and NO gas was measured.
Results: see figure.
Conclusions: Leptomeningeal and adipose arterioles obtained by rapid autopsy remain functionally viable for testing. Cadaver leptomeningeal and adipose arterioles as well as ex-vivo adipose arterioles from living subjects had similar responses, demonstrating Aβ42-induced endothelial dysfunction, likely through reduced NO generation. We demonstrate the feasibility of using cadaver vessels to study the vascular component of AD and validate the use of peripheral microvasculature to mimic central brain vascular responses. The human vascular models used may be exploited to study AD and potentially bridge the translational gap between animal studies and human clinical trials.
- © 2013 by American Heart Association, Inc.