AMYLOID-Beta PEPTIDES DISRUPT BLOOD-BRAIN BARRIER PROPERTIES BY ACTING DIRECTLY ON BRAIN ENDOTHELIAL CELLS AND INDIRECTLY THROUGH INTERACTION WITH GLIAL CELLS.

POMILIO C; PRESA J; VINUESA A; GREGOSA A; KIM KS; BEAUQUIS J; SARAVIA F

Mar del Plata

Congreso; Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

Alzheimer?s disease (AD) is the leading cause of dementia. It is characterized by the presence of intraneuronal deposits of Tau and the extracellular accumulation of Amyloid- β (Aβ) fibrils, composed mainly of Aβ1-40 and Aβ1-42 peptides. Moreover, glial activation, neuroinflammation and alterations on brain vasculature were evidencedboth in patients and animal models of AD. In this study, we hypothesized that Aβ1-40 (mostly present in perivascular deposits)can directly affect endothelial cells, while Aβ1-42 (the principal component of parenchymal deposits) act mainly through modulating glial activation. To test this, we employed human brain microvascularendothelial cells (HBMEC cell line) exposed to Aβ1-40 and Aβ1-42. Acute exposition to both fibrilar and soluble Aβ-40 (but not Aβ1-42) induced activation of HBMEC as it was shown by nuclear translocation of NFkB. This activation was mediated by interaction with the Receptor for Advanced Glication End-Products (RAGE), as it was prevented 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 and also Aβ1-42, activated endothelial cells in a RAGE-dependent way. However, conditioned medium from microglialcells (BV-2 cell line) activated endothelial cells when they were exposed either to fibrilar Aβ1-40 or Aβ1-42, in a RAGE-independent way. Employing 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 concludethat disruption of blood-brain barrier properties can be caused directly by the action of Aβ peptides but also indirectly by the activationof glial cells. In both cases, the damage-associated receptor RAGE plays a critical role on endothelial activation.