Loss of direct vascular contact to astrocytes in the hippocampus as an initial event in Alzheimer’s disease. Evidence from patients, in vivo and in vitro experimental models.

Abstract

Abstract Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and also around vasculature. The hippocampus -a complex brain structure with a crucial role in learning and memory- is considered a target in the pathology. However, there is scarce information regarding vascular changes during the AD neurodegenerative process in this vulnerable structure, that is a unique in terms of vasculature features. Our aim was to evaluate hippocampal vascular alterations in AD patients and PDAPP-J20 mice -model of AD- and define the impact of Aβ40 and Aβ42 on endothelial activation. We found loss of physical astrocyte-endothelium interaction in the hippocampus of AD subjects as compared to non-AD donors together with decreased vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were early altered in PDAPP-J20 mice, before vascular morphological changes or blood-brain barrier disruption were evident. At later stages, PDAPP-J20 mice showed decreased hippocampal vascular density and extravasation of fluorescent tracers, indicating vascular and BBB dysfunction. In vitro studies showed that exposure of human brain microvascular endothelial cells (HBMEC) to soluble Aβ40 was sufficient to promote NFκB translocation to the nucleus, leading to a reduction in occludin levels. These changes were prevented by treatment of HBMEC with an inhibitor of the membrane receptor for advanced glycation endproducts (RAGE). Additional results suggest that Aβ42 acts indirectly on the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature during Alzheimer's disease.