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

• Published in: Journal of neuroscience methods 2014-09, Vol.235, p.123-129
• Main Authors: Truran, Seth, Franco, Daniel A., Roher, Alex E., Beach, Thomas G., Burciu, Camelia, Serrano, Geidy, Maarouf, Chera L., Schwab, Sara, Anderson, Jenna, Georges, Joseph, Reaven, Peter, Migrino, Raymond Q.
• Format: Article
• Language: English
• Subjects: Abdomen - blood supply; Acetylcholine - pharmacology; Adipose Tissue - blood supply; Aged; Aged, 80 and over; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid; Amyloid beta-Peptides; Arterioles - physiopathology; Endothelial Cells - physiology; Endothelial function; Female; Humans; Male; Meninges - blood supply; Microvessels; Middle Aged; Oxidative Stress - physiology; Papaverine - pharmacology; Peptide Fragments; Reactive Oxygen Species - metabolism; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vasodilator Agents - pharmacology
• ISSN: 0165-0270; 1872-678X
• DOI: 10.1016/j.jneumeth.2014.06.014

•The lack of treatment for AD emphasizes need for novel models to study the disease.•Donor leptomeningeal arterioles show variable ability to respond to vasodilators.•Aβ1-42 induces similar endothelial dysfunction in leptomeningeal and adipose arterioles.•Aβ1–42 peptide induces human arteriole oxidative and nitrative stress.•Human adipose and leptomeningeal arterioles may be useful tissue models for AD. 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 β-amyloid peptide induces endothelial dysfunction and oxidative stress in human microvasculature and that response will be similar between peripheral adipose and brain leptomeningeal arterioles. Abdominal subcutaneous arterioles from living human subjects (n=17) and cadaver leptomeningeal arterioles (n=6) from rapid autopsy were exposed to Aβ1–42 (Aβ) 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. Methods described allow direct investigation of human microvessel functional response that cannot be replicated by human noninvasive imaging or post-mortem histology. Adipose arterioles exposed to 2μM Aβ showed impaired dilation to acetylcholine that was reversed by antioxidant polyethylene glycol superoxide dismutase (PEG-SOD) (Aβ-60.9±6%, control-93.2±1.8%, Aβ+PEGSOD-84.7±3.9%, both p