Aβ1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling

被引:209
作者
Kook, Sun-Young [1 ]
Hong, Hyun Seok [1 ,2 ]
Moon, Minho [1 ]
Ha, Chang Man [3 ]
Chang, Sunghoe [3 ]
Mook-Jung, Inhee [1 ]
机构
[1] Seoul Natl Univ, Coll Med, Dept Biochem & Biomed Sci, Seoul 110799, South Korea
[2] Medifron DBT, Ansan 425120, Gyeongi Do, South Korea
[3] Seoul Natl Univ, Coll Med, Dept Physiol & Biomed Sci, Seoul 110799, South Korea
基金
新加坡国家研究基金会;
关键词
CEREBRAL AMYLOID ANGIOPATHY; MICROVESSEL ENDOTHELIAL-CELLS; ALZHEIMERS-DISEASE; TRANSGENIC MICE; OXIDATIVE STRESS; UP-REGULATION; ANIMAL-MODEL; BETA PROTEIN; RAGE; PERMEABILITY;
D O I
10.1523/JNEUROSCI.6102-11.2012
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The blood-brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca2+ 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 (A beta) and mediate A beta transport across the BBB, contributing to the deposition of A beta in the brain. However, molecular mechanisms underlying A beta-RAGE interaction-induced alterations in the BBB have not been identified. We found that A beta(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 A beta(1-42)-induced changes in ZO-1, suggesting that A beta-RAGE interactions alter TJ proteins through the Ca2+-calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near A beta 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 A beta-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.
引用
收藏
页码:8845 / 8854
页数:10
相关论文
共 45 条
[1]   Overactivation of calcineurin induced by amyloid-beta and prion proteins [J].
Agostinho, Paula ;
Lopes, Joao P. ;
Velez, Zelia ;
Oliveira, Catarina R. .
NEUROCHEMISTRY INTERNATIONAL, 2008, 52 (06) :1226-1233
[2]   Interactions of beta-amyloids with the blood-brain barrier [J].
Banks, WA ;
Kastin, AJ ;
Maness, LM ;
Banks, MF ;
Shayo, M ;
McLay, RN .
CEREBROVASCULAR PATHOLOGY IN ALZHEIMER'S DISEASE, 1997, 826 :190-199
[3]   Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines:: an absolute requirement for transcription factor NF-κB [J].
Bond, M ;
Fabunmi, RP ;
Baker, AH ;
Newby, AC .
FEBS LETTERS, 1998, 435 (01) :29-34
[4]   Tight junction protein expression and barrier properties of immortalized mouse brain microvessel endothelial cells [J].
Brown, Rachel C. ;
Morris, Andrew P. ;
O'Neil, Roger G. .
BRAIN RESEARCH, 2007, 1130 (01) :17-30
[5]   RAGE regulates BACE1 and Aβ generation via NFAT1 activation in Alzheimer's disease animal model [J].
Cho, H. J. ;
Son, S. M. ;
Jin, S. M. ;
Hong, H. S. ;
Shin, D. H. ;
Kim, S. J. ;
Huh, K. ;
Mook-Jung, I. .
FASEB JOURNAL, 2009, 23 (08) :2639-2649
[6]  
Claudio L, 1996, ACTA NEUROPATHOL, V91, P6
[7]   Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability [J].
Dahlgren, KN ;
Manelli, AM ;
Stine, WB ;
Baker, LK ;
Krafft, GA ;
LaDu, MJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (35) :32046-32053
[8]   Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine [J].
De Felice, Fernanda G. ;
Velasco, Pauline T. ;
Lambert, Mary P. ;
Viola, Kirsten ;
Fernandez, Sara J. ;
Ferreira, Sergio T. ;
Klein, William L. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (15) :11590-11601
[9]   RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain [J].
Deane, R ;
Yan, SD ;
Submamaryan, RK ;
LaRue, B ;
Jovanovic, S ;
Hogg, E ;
Welch, D ;
Manness, L ;
Lin, C ;
Yu, J ;
Zhu, H ;
Ghiso, J ;
Frangione, B ;
Stern, A ;
Schmidt, AM ;
Armstrong, DL ;
Arnold, B ;
Liliensiek, B ;
Nawroth, P ;
Hofman, F ;
Kindy, M ;
Stern, D ;
Zlokovic, B .
NATURE MEDICINE, 2003, 9 (07) :907-913
[10]   Molecular mechanisms of cyclosporin a inhibition of the cytokine-induced matrix metalloproteinase-9 in glomerular mesangial cells [J].
Doller, Anke ;
Akool, El-Sayed ;
Mueller, Roswitha ;
Gutwein, Paul ;
Kurowski, Christine ;
Pfeilschifter, Josef ;
Eberhardt, Wolfgang .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2007, 18 (02) :581-592