title: Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1.
abstract: Alterations of the renin-angiotensin system have been implicated in the pathogenesis of Alzheimer's disease. We tested the efficacy of losartan (10 mg/kg/day for three months), a selective angiotensin II type 1 receptor antagonist, in alleviating cerebrovascular and cognitive deficits in double-transgenic mice (six months at endpoint) that overexpress a mutated form of the human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of the transforming growth factor-β1, thereafter named A/T mice. Losartan rescued cerebrovascular reactivity, particularly the dilatory responses, but failed to attenuate astroglial activation and to normalize the neurovascular uncoupling response to sensory stimulation. The cognitive deficits of A/T mice were not restored by losartan nor were the increased brain levels of soluble and insoluble Aβ1-40and Aβ1-42peptides normalized. Our results are the first to demonstrate the capacity of losartan to improve cerebrovascular reactivity in an Alzheimer's disease mouse model of combined Aβ-induced vascular oxidative stress and transforming growth factor-β1-mediated vascular fibrosis. These data suggest that losartan may be promising for restoring cerebrovascular function in patients with vascular diseases at risk for vascular dementia or Alzheimer's disease. However, a combined therapy may be warranted for rescuing both vascular and cognitive deficits in a multifaceted pathology like Alzheimer's disease.
authors.affiliation: 1 Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Panayiota
authors.initials: P
authors.lastname: Papadopoulos
authors.affiliation: 1 Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Xin-Kang
authors.initials: XK
authors.lastname: Tong
authors.affiliation: 2 Institute of Cell Biology, University of Bern, Bern, Switzerland.
authors.forename: Hans
authors.initials: H
authors.lastname: Imboden
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 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D006801:Humans; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D047228:Angiotensin II Type 1 Receptor Blockers; D053773:Transforming Growth Factor beta1; D019808:Losartan
keywords: Memory; amyloidosis; angiotensin II; angiotensin II type 1 receptor; renin-angiotensin system; small vessel disease