title: Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease.
abstract: The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Brice
authors.initials: B
authors.lastname: Ongali
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Nektaria
authors.initials: N
authors.lastname: Nicolakakis
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Xing-Kang
authors.initials: XK
authors.lastname: Tong
authors.affiliation: Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Tahar
authors.initials: T
authors.lastname: Aboulkassim
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, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy / Q000209:etiology; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000209:etiology*; D002802:Cholinesterases / Q000378:metabolism; D004195:Disease Models, Animal; D004338:Drug Combinations; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000959:Antihypertensive Agents; D004338:Drug Combinations; D005904:Glial Fibrillary Acidic Protein; D004656:Enalapril; D002802:Cholinesterases; D019808:Losartan
keywords: APP mice; Alzheimer’s disease; angiotensin II; angiotensin converting enzyme inhibitors (ACEi); enalapril; losartan