Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1.

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 Aβ1–40 and Aβ1–42 peptides normalized. Our results are the first to demonstrate the capacity of losartan to improve cerebrovascular reactivity in an Alzheimer's disease...