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

• Published in: Experimental neurology Vol. 213; no. 1; pp. 114 - 121
• Main Authors: Tang, Sung-Chun, Lathia, Justin D., Selvaraj, Pradeep K., Jo, Dong-Gyu, Mughal, Mohamed R., Cheng, Aiwu, Siler, Dominic A., Markesbery, William R., Arumugam, Thiruma V., Mattson, Mark P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.09.2008; Elsevier
• Subjects: 4-hydroxynonenal; Aged; Aged, 80 and over; Aldehydes - metabolism; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Amyloid β-peptide; Animals; Apoptosis - drug effects; Biological and medical sciences; Brain - metabolism; Brain - pathology; Caspase 3 - drug effects; Caspase 3 - metabolism; Cell death; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Humans; JNK Mitogen-Activated Protein Kinases - drug effects; JNK Mitogen-Activated Protein Kinases - metabolism; Lipid Peroxidation; Male; Medical sciences; Membrane Lipids - metabolism; Mice; Mice, Knockout; Nerve Degeneration - chemically induced; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurology; Neuron; Oxidative Stress - drug effects; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Signal Transduction - drug effects; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Toll-like receptors; Neuron; Cell death; Amyloid β-peptide; 4-hydroxynonenal; Nervous system diseases; Peptides; Lipids; Amyloid; Apoptosis; Peroxidation; Biological receptor
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2008.05.014

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 β-peptide (Aβ1–42) or the lipid peroxidation product 4-hydroxynonenal (HNE). Neuronal apoptosis triggered by Aβ 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 Aβ 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 Aβ and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD.