Amyloid-β peptides disrupt blood-brain barrier properties by acting directly on brain endothelial cells and indirectly through interaction with glial cells.

CARLOS POMILIO; JESSICA PRESA; ÁNGELES VINUESA; AMAL GREGOSA; BEAUQUIS JUAN; FLAVIA SARAVIA

Mar del Plata

Congreso; Reunión anual de la Sociedad Argentina de Investigaciones Clínicas; 2018

Sociedad Argentina de Investigaciones Clínicas

Alzheimer?s disease (AD) is the leading cause of dementia. It is characterized by intraneuronal deposits of Tau and the extracellular accumulation of Amyloid- β (Aβ) deposits, composed mainly of Aβ 1-40 and Aβ1-42 peptides. Moreover, glial activation, neuroinflammation and alterations on brain vasculature were evidenced in both patients and animal models of AD. In this study, we addressed the role of Aβ1-40 (mostly present in perivascular deposits) and Aβ1-42 (the principal component of parenchymal deposits) in the activation of endothelial cells, in close association with glial cells. We exposed human brain microvascular endothelial cells (HBMEC cell line) to Aβ1-40 and Aβ1-42. Acute exposition to both fibrilar and soluble Aβ1-40 (but not Aβ1-42) induced activation of HBMEC evidenced by nuclear translocation of NFkB. This activation was mediated by interaction with the Receptor for Advanced Glication End-Products (RAGE), as it was prevented in part by the use of a competitive inhibitor. The nuclear translocation of NfkB was associated with a reduced location of the tight junction protein Occludin at the plasmatic membrane. Moreover, the conditioned medium from astrocytes (C6 cell line) exposed to fibrilar Aβ1-40 or Aβ1-42, activated endothelial cells in a RAGE-dependent way. However, conditioned medium from microglial cells (BV-2 cell line) activated endothelial cells when they were exposed either to fibrilar Aβ1-40, Aβ1-42 or vehicle, in a RAGE-independent way. In the hippocampus of young PDAPP mice, an animal model of AD, we detected an early reduction in the proportion of astrocytes in direct contact with hippocampal vasculature, suggesting that astroglial-endothelial interaction can be altered in pre-symptomatic stages of AD. We conclude that disruption of blood-brain barrier properties can be caused directly by the action of Aβ peptides but also indirectly by the activation of glial cells. In both cases, the damage-associated receptor RAGE plays a critical role on endothelial activation.