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Aβ1-42 oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins.
- Source :
-
Journal of Neurochemistry . Jul2015, Vol. 134 Issue 2, p382-393. 12p. - Publication Year :
- 2015
-
Abstract
- Accumulating evidence indicates that abnormal deposition of amyloid-β (Ab) peptide in the brain is responsible for endothelial cell damage and consequently leads to blood-brain barrier (BBB) leakage. However, the mechanisms underlying BBB disruption are not well described. We employed an monolayer BBB model comprising bEnd.3 cell and found that BBB leakage was induced by treatment with Aβ1-42, and the levels of tight junction (TJ) scaffold proteins (ZO-1, Claudin-5, and Occludin) were decreased. Through comparisons of the effects of the different components of Aβ1-42, including monomer (Aβ1-42-Mono), oligomer (Aβ1-42-Oligo), and fibril (Aβ1-42-Fibril), our data confirmed that Aβ1-42-Oligo is likely to be the most important damage factor that results in TJ damage and BBB leakage in Alzheimer's disease. We found that the incubation of bEnd.3 cells with Aβ1-42 significantly up-regulated the level of receptor for advanced glycation end-products (RAGE). Co-incubation of a polyclonal antibody to RAGE and Aβ1-42-Oligo in bEnd.3 cells blocked RAGE suppression of Aβ1-42-Oligo-induced alterations in TJ scaffold proteins and reversed Aβ1-42-Oligoinduced up-regulation of RAGE, matrix metalloproteinase (MMP)-2, and MMP-9. Furthermore, we found that these effects induced by Aβ1-42-Oligo treatment were effectively suppressed by knockdown of RAGE using small interfering RNA (siRNA) transfection. We also found that GM 6001, a broad-spectrum MMP inhibitor, partially reversed the Aβ1-42-Oligo-induced inhibitor effects in bEnd.3 cells. Thus, these results suggested that RAGE played an important role in Abinduced BBB leakage and alterations of TJ scaffold proteins, through a mechanism that involved up-regulation of MMP-2 and MMP-9. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00223042
- Volume :
- 134
- Issue :
- 2
- Database :
- Academic Search Index
- Journal :
- Journal of Neurochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 108763642
- Full Text :
- https://doi.org/10.1111/jnc.13122