Adipose and leptomeningeal arteriole endothelial dysfunction induced by β-amyloid peptide: A practical human model to study Alzheimer's disease vasculopathy

Background: Evidence point to vascular dysfunction and hypoperfusion as early abnormalities in Alzheimer's disease (AD); probing their mechanistic bases can lead to new therapeutic approaches. We tested the hypotheses that beta-amyloid peptide induces endothelial dysfunction and oxidative stress in human microvasculature and that response will be similar between peripheral adipose and brain leptomeningeal arterioles. New method: Abdominal subcutaneous arterioles from living human subjects (n = 17) and cadaver leptomeningeal arterioles (n = 6) from rapid autopsy were exposed to A beta-42 (A beta) for 1-h and dilation response to acetylcholine/papaverine were measured and compared to baseline response. Adipose arteriole reactive oxygen species (ROS) production and nitrotyrosine content were measured. Comparison with existing methods: Methods described allow direct investigation of human microvessel functional response that cannot be replicated by human noninvasive imaging or post-mortem histology. Results: Adipose arterioles exposed to 2 mu M A beta showed impaired dilation to acetylcholine that was reversed by antioxidant polyethylene glycol superoxide dismutase (PEG-SOD) (A beta-60.9 +/- 6%, control-93.2 +/- 1.8%, A beta+PEGSOD-84.7 +/- 3.9%, both p<0.05 vs. A beta). A beta caused reduced dilation to papaverine. Ap increased adipose arteriole ROS production and increased arteriole nitrotyrosine content. Leptomeningeal arterioles showed similar impaired response to acetylcholine when exposed to A beta (43.0 +/- 6.2% versus 81.1 +/- 5.7% control, p<0.05). Conclusion: A beta exposure induced adipose arteriole endothelial and non-endothelial dysfunction and oxidative stress that were reversed by antioxidant treatment. A beta-induced endothelial dysfunction was similar between peripheral adipose and leptomeningeal arterioles. Ex vivo living adipose and cadaver leptomeningeal arterioles are viable, novel and practical human tissue models to study Alzheimer's vascular pathophysiology. Published by Elsevier B.V.