Journal
EXPERIMENTAL NEUROLOGY
Volume 213, Issue 1, Pages 114-121Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2008.05.014
Keywords
toll-like receptors; amyloid beta-peptide; 4-hydroxynonenal; neuron; cell death
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Funding
- Intramural Research Program of the National Institute on Aging
- National Institutes of Health
- NATIONAL INSTITUTE ON AGING [ZIAAG000313, ZIAAG000332, ZIAAG000312] Funding Source: NIH RePORTER
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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.
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