title: Adipose and leptomeningeal arteriole endothelial dysfunction induced by β-amyloid peptide: a practical human model to study Alzheimer's disease vasculopathy.
abstract: 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 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.
  
  
  METHODS
  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
  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 μM 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<0.05 vs. Aβ). Aβ caused reduced dilation to papaverine. Aβ increased adipose arteriole ROS production and increased arteriole nitrotyrosine content. Leptomeningeal arterioles showed similar impaired response to acetylcholine when exposed to Aβ (43.0 ± 6.2% versus 81.1 ± 5.7% control, p<0.05).
  
  
  CONCLUSIONS
  Aβ exposure induced adipose arteriole endothelial and non-endothelial dysfunction and oxidative stress that were reversed by antioxidant treatment. Aβ-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.
authors.affiliation: Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85012, USA.
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.affiliation: Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85012, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.affiliation: Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA.
authors.forename: Alex E
authors.initials: AE
authors.lastname: Roher
authors.affiliation: Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85012, USA.
authors.forename: Camelia
authors.initials: C
authors.lastname: Burciu
authors.affiliation: Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA.
authors.forename: Geidy
authors.initials: G
authors.lastname: Serrano
authors.affiliation: Banner Sun Health Research Institute, 10515 W Santa Fe Dr, Sun City, AZ 85351, USA.
authors.forename: Chera L
authors.initials: CL
authors.lastname: Maarouf
authors.affiliation: Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85012, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Schwab
authors.affiliation: University of Arizona College of Medicine, 550 E. Van Buren, Phoenix, AZ 85004, USA.
authors.forename: Jenna
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Georges
authors.affiliation: Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85012, USA; University of Arizona College of Medicine, 550 E. Van Buren, Phoenix, AZ 85004, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Reaven
authors.affiliation: Phoenix Veterans Affairs Health Care System, 650 E. Indian School Road, Phoenix, AZ 85012, USA; University of Arizona College of Medicine, 550 E. Van Buren, Phoenix, AZ 85004, USA. Electronic address: raymond.migrino@va.gov.
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
mesh_terms: D000005:Abdomen / Q000098:blood supply; D000109:Acetylcholine / Q000494:pharmacology; D000273:Adipose Tissue / Q000098:blood supply*; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides; D001160:Arterioles / Q000503:physiopathology*; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008578:Meninges / Q000098:blood supply*; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology; D010208:Papaverine / Q000494:pharmacology; D010446:Peptide Fragments; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C075222:amyloid beta-protein (1-42); C002744:3-nitrotyrosine; D014443:Tyrosine; D010208:Papaverine; D000109:Acetylcholine
keywords: Alzheimer's disease; Amyloid; Endothelial function; Microvessels