RGD Reference Report - Abeta1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling. - Rat Genome Database

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Abeta1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling.

Authors: Kook, SY  Hong, HS  Moon, M  Ha, CM  Chang, S  Mook-Jung, I 
Citation: Kook SY, etal., J Neurosci. 2012 Jun 27;32(26):8845-54.
RGD ID: 6784502
Pubmed: PMID:22745485   (View Abstract at PubMed)
PMCID: PMC6622350   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.6102-11.2012   (Journal Full-text)

The blood-brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca(2+) homeostasis and breakdown of the BBB have been implicated in the pathogenesis of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE) is known to interact with amyloid beta-peptide (Abeta) and mediate Abeta transport across the BBB, contributing to the deposition of Abeta in the brain. However, molecular mechanisms underlying Abeta-RAGE interaction-induced alterations in the BBB have not been identified. We found that Abeta(1-42) induces enhanced permeability, disruption of zonula occludin-1 (ZO-1) expression in the plasma membrane, and increased intracellular calcium and matrix metalloproteinase (MMP) secretion in cultured endothelial cells. Neutralizing antibodies against RAGE and inhibitors of calcineurin and MMPs prevented Abeta(1-42)-induced changes in ZO-1, suggesting that Abeta-RAGE interactions alter TJ proteins through the Ca(2+)-calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near Abeta plaque-deposited areas, elevated RAGE expression, and enhanced MMP secretion in microvessels of the brains of 5XFAD mice, an animal model for AD. We have identified a potential molecular pathway underlying Abeta-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  ISOAger (Mus musculus)6784502; 6784502 RGD 
Alzheimer's disease  IEP 6784502 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ager  (advanced glycosylation end product-specific receptor)

Genes (Mus musculus)
Ager  (advanced glycosylation end product-specific receptor)

Genes (Homo sapiens)
AGER  (advanced glycosylation end-product specific receptor)


Additional Information