MICROVASCULAR ALTERATIONS IN THE HIPPOCAMPUS OF ALZHEIMER’S DISEASE PATIENTS AND A TRANSGENIC MOUSE MODEL. FOCUS ON ENDOTHELIAL EARLY INVOLVEMENT

SARAVIA, F.; PRESA, J.; BEAUQUIS, J.; POMILIO, C.

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2023

Alzheimer’s disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and vasculature. Although vascular alterations are intrinsic to the progression of AD, it is still debated whether these changes are a cause or a consequence of amyloid pathology. In addition, there is limited information regarding vascular changes during the neurodegenerative process of AD in the hippocampus, a crucial structure for learning and memory functions with unique vascular characteristics and, also, an important target in AD. In this symposium, we will present data on hippocampal vascular alterations in AD patients and PDAPP-J20 mice -model of AD- and define the impact of amyloid peptides Aβ40 and Aβ42 on in vitro endothelial activation. We found decreased vascular density and reduced physical astrocyte-endothelium interaction in the hippocampus of AD subjects as compared to age-matched controls. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered at an early age in PDAPP-J20 mice, before vascular morphological changes or blood-brain barrier (BBB) disruption. At later stages, PDAPP-J20 mice showed decreased hippocampal vascular density and extravasation of fluorescent tracers, indicating vascular and BBB compromise. In vitro studies showed that exposure of human brain microvascular endothelial cells (HBMEC) to soluble Aβ40 was sufficient to a) prompt a decrease in the transendothelial electrical resistance as assessed in a cell monolayer cultured in a transwell assay; b) 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). Conditioned media obtained from astrocytes exposed to Aβ42 had a similar effect on endothelial cells, indicating that Aβ42 acts indirectly on the endothelium by inducing astrocytic factors; c) induce a dysregulated proteostasis and activation of endoplasmic reticulum stress pathway. In summary, our results from human and mouse brain samples provide original evidence for the critical involvement of the hippocampal vasculature in Alzheimer’s disease. Our in vitro data contribute to elucidate the molecular pathways implicated and shed light on new therapeutic strategies.