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

POMILIO, CARLOS; PRESA, JESSICA; VINUESA, ANGELES; BEAUQUIS J; SARAVIA F

Mar del Plata

Congreso; Reunion Anual de la Sociedad Argentina de Investigacion Clinica; 2018

SAIC

Alzheimer?s disease (AD) is the leading cause of dementia. It ischaracterized by the presence of intraneuronal deposits of Tau andthe extracellular accumulation of Amyloid- β (Aβ) fibrils, composedmainly 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, wehypothesized that Aβ1-40 (mostly present in perivascular deposits)can directly affect endothelial cells, while Aβ1-42 (the principalcomponent of parenchymal deposits) act mainly through modulatingglial activation. To test this, we employed human brain microvascularendothelial cells (HBMEC cell line) exposed to Aβ1-40 andAβ1-42. Acute exposition to both fibrilar and soluble Aβ-40 (but notAβ1-42) induced activation of HBMEC as it was shown by nucleartranslocation of NFkB. This activation was mediated by interactionwith the Receptor for Advanced Glication End-Products (RAGE), asit was prevented by the use of a competitive inhibitor. The nucleartranslocation of NfkB was associated with a reduced location of thetight junction protein Occludin at the plasmatic membrane. Moreover,the conditioned medium from astrocytes (C6 cell line) exposedto fibrilar Aβ1-40 and also Aβ1-42, activated endothelial cells in aRAGE-dependent way. However, conditioned medium from microglialcells (BV-2 cell line) activated endothelial cells when they wereexposed either to fibrilar Aβ1-40 or Aβ1-42, in a RAGE-independentway. Employing PDAPP mice, an animal model of AD, we detectedan early reduction in the proportion of astrocytes in direct contactwith hippocampal vasculature, suggesting that astroglial-endothelialinteraction can be altered in pre-symptomatic stages of AD. We concludethat disruption of blood-brain barrier properties can be causeddirectly by the action of Aβ peptides but also indirectly by the activationof glial cells. In both cases, the damage-associated receptorRAGE plays a critical role on endothelial activation.