title: Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.
abstract: Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Brice
authors.initials: B
authors.lastname: Ongali
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Nektaria
authors.initials: N
authors.lastname: Nicolakakis
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Tahar
authors.initials: T
authors.lastname: Aboulkassim
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Panayiota
authors.initials: P
authors.lastname: Papadopoulos
authors.affiliation: Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montréal, QC H3A 2B4, Canada; Douglas Hospital Research Centre, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rosa-Neto
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lecrux
authors.affiliation: Institute of Cell Biology, University of Bern, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Imboden
authors.affiliation: Laboratory of Cerebrovascular Research, McGill University, Montréal, QC H3A 2B4, Canada. Electronic address: edith.hamel@mcgill.ca.
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D047228:Angiotensin II Type 1 Receptor Blockers; D019332:Endothelin-1; D004791:Enzyme Inhibitors; C000589294:N(omega)-(2-methoxyethyl)arginine; D001120:Arginine; D019808:Losartan
keywords: AT1 receptor; AT4 receptor; Amyloid; Angiotensin receptor blocker (ARB); FDG-PET; Insulin-regulated aminopeptidase (IRAP); Memory; Oxidative stress