Age-dependent neurovascular dysfunction and damage in a mouse model of cerebral amyloid angiopathy

Abstract

Background and Purpose: Accumulation of amyloid-β in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established. METHODS-: We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild-type littermates equipped with a cranial window. RESULTS-: Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium-dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenuated. However, at 18 and 24 months, all cerebrovascular responses were markedly reduced. At this time, there was evidence of cerebrovascular amyloid deposition, smooth muscle fragmentation, and pericyte loss. Neocortical superfusion with the free radical scavenger manganic(I-II)meso-tetrakis(4- benzoic acid) porphyrin rescued endothelium-dependent responses and functional hyperemia completely at 3 months but only partially at 18 months. CONCLUSIONS-: Tg-SwDI mice exhibit a profound age-dependent cerebrovascular dysfunction, involving multiple regulatory mechanisms. Early in the disease process, oxidative stress is responsible for most of the vascular dysfunction, but with advancing disease structural alterations of the vasomotor apparatus also play a role. Early therapeutic interventions are likely to have the best chance to counteract the deleterious vascular effects of cerebral amyloid angiopathy. © 2014 American Heart Association, Inc.