title: Proteomic differences in brain vessels of Alzheimer's disease mice: Normalization by PPARγ agonist pioglitazone.
abstract: Cerebrovascular insufficiency appears years prior to clinical symptoms in Alzheimer's disease. The soluble, highly toxic amyloid-β species, generated from the amyloidogenic processing of amyloid precursor protein, are known instigators of the chronic cerebrovascular insufficiency observed in both Alzheimer's disease patients and transgenic mouse models. We have previously demonstrated that pioglitazone potently reverses cerebrovascular impairments in a mouse model of Alzheimer's disease overexpressing amyloid-β. In this study, we sought to characterize the effects of amyloid-β overproduction on the cerebrovascular proteome; determine how pioglitazone treatment affected the altered proteome; and analyze the relationship between normalized protein levels and recovery of cerebrovascular function. Three-month-old wildtype and amyloid precursor protein mice were treated with pioglitazone- (20 mg/kg/day, 14 weeks) or control-diet. Cerebral arteries were surgically isolated, and extracted proteins analyzed by gel-free and gel-based mass spectrometry. 193 cerebrovascular proteins were abnormally expressed in amyloid precursor protein mice. Pioglitazone treatment rescued a third of these proteins, mainly those associated with oxidative stress, promotion of cerebrovascular vasocontractile tone, and vascular compliance. Our results demonstrate that amyloid-β overproduction perturbs the cerebrovascular proteome. Recovery of cerebrovascular function with pioglitazone is associated with normalized levels of key proteins in brain vessel function, suggesting that pioglitazone-responsive cerebrovascular proteins could be early biomarkers of Alzheimer's disease.
authors.affiliation: 1 Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: AmanPreet
authors.initials: A
authors.lastname: Badhwar
authors.affiliation: 2 Human Health Therapeutics, National Research Council of Canada, Ottawa, Ontario, Canada.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brown
authors.affiliation: 2 Human Health Therapeutics, National Research Council of Canada, Ottawa, Ontario, Canada.
authors.forename: Danica B
authors.initials: DB
authors.lastname: Stanimirovic
authors.affiliation: 2 Human Health Therapeutics, National Research Council of Canada, Ottawa, Ontario, Canada.
authors.forename: Arsalan S
authors.initials: AS
authors.lastname: Haqqani
authors.affiliation: 1 Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000502:physiology; D000818:Animals; D015415:Biomarkers; D001808:Blood Vessels / Q000737:chemistry*; D001921:Brain / Q000098:blood supply*; D002536:Cerebral Arteries / Q000737:chemistry; D002561:Cerebrovascular Disorders / Q000139:chemically induced*; D004195:Disease Models, Animal; D051379:Mice; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D020543:Proteome / Q000187:drug effects*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D047495:PPAR gamma; D020543:Proteome; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Amyloid peptide; cerebral artery; oxidative stress; proliferator-activated receptor gamma; vascular biomarkers