Abstract
Clinical and experimental evidence point to a possible role of ă cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse ă model of AD expresses human amyloid precursor protein and presenilin ă genes with mutations found in AD patients. It remains unknown whether ă amyloid deposition driven by these mutations is associated with ă cerebrovascular changes. ă 5xFAD and wild type mice (2 to 12 months old; M2 to M12) were used. ă Thinned skull in vivo 2-photon microscopy was used to determine A beta ă accumulation on leptomeningeal or superficial cortical vessels over ă time. Parenchymal microvascular damage was assessed using ă FITC-microangiography. Collagen-IV and CD31 were used to stain basal ă lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were ă used to visualize A beta accumulation in living mice or in fixed brain ă tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at ă the vasculature was rendered using confocal microscopy. Platelet-derived ă growth factor receptor beta (PDGFR(3) staining was used to visualize ă perivascular pericytes. ă In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular ă deposits on leptomeningeal and penetrating cortical vessels in 5xFAD ă mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits ă were visible in vivo at M3 and aggravated over time. Progressive ă microvascular damage was concomitant to parenchymal A beta plaque ă accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice ă presented with sporadic FITC-albumin leakages at M4 becoming more ă prevalent at M9 and M12.3D colocalization showed inflammatory IBA1(+) ă microglia proximal to microvascular FITC-albumin leaks. The number of ă perivascular PDGFR beta(+) pericytes was significantly decreased at M4 ă in the fronto-parietal cortices, with a trend decrease observed in the ă other structures. At M9-M12, PDGFR beta(+) pericytes displayed ă hypertrophic perivascular ramifications contiguous to reactive ă microglia. ă Cerebral amyloid angiopathy and microvascular inflammation occur in ă 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect ă of cerebrovascular pharmacology in AD is discussed. (C) 2016 Elsevier ă Inc. All rights reserved.