Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal

被引:227
作者
Tang, Sung-Chun [1 ,2 ,3 ]
Lathia, Justin D. [1 ]
Selvaraj, Pradeep K. [6 ]
Jo, Dong-Gyu [1 ,4 ]
Mughal, Mohamed R. [1 ]
Cheng, Aiwu [1 ]
Siler, Dominic A. [1 ]
Markesbery, William R. [5 ]
Arumugam, Thiruma V. [6 ]
Mattson, Mark P. [1 ,7 ]
机构
[1] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA
[2] Natl Taiwan Univ Hosp, Stoke Ctr, Dept Neurol, Taipei, Taiwan
[3] Natl Taiwan Univ Hosp, Dept Neurol, Yun Liin Branch, Taipei, Taiwan
[4] Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea
[5] Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA
[6] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Sch Pharm, Amarillo, TX USA
[7] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
基金
美国国家卫生研究院;
关键词
toll-like receptors; amyloid beta-peptide; 4-hydroxynonenal; neuron; cell death;
D O I
10.1016/j.expneurol.2008.05.014
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We recently found that neurons express several TLRs, and that the levels of TLR2 and TLR4 are increased in neurons in response to energy deprivation. Here we report that TLR4 expression increases in neurons when exposed to amyloid beta-peptide (A beta 1-42) or the lipid pet-oxidation product 4-hydroxynonenal (HNE). Neuronal apoptosis triggered by A beta and HNE was mediated by jun N-terminal kinase (JNK); neurons from TLR4 mutant mice exhibited reduced JNK and caspase-3 activation and were protected against apoptosis induced by A beta and HNE. Levels of TLR4 were decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched Control Subjects, possibly as the result of loss of neurons expressing TLR4. Our findings Suggest that TLR4 signaling increases the vulnerability of neurons to A beta and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD. Published by Elsevier Inc.
引用
收藏
页码:114 / 121
页数:8
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