Human amylin induces "apoptotic" pattern of gene expression concomitant with cortical neuronal apoptosis.
Amylin forms large beta-pleated neurotoxic oligomers but shows only 38% sequence similarity to A beta. As patterns of gene expression during neuronal apoptosis appear stimulus and cell type specific, we compared the pattern of amylin-induced gene expression in rat cortical neurons with that shown previously to be induced by A beta in order to evaluate whether these two peptides with different primary but similar secondary structure induce apoptosis similarly. Morphologic and quantitative measures of cell death show widespread apoptotic death after amylin treatment. Amylin treatment results in time- and concentration-dependent inductions of oxidative stress genes, such as cox-2 and IkappaB-alpha. "Apoptotic" genes are also induced in a time- and concentration-dependent manner, including c-jun, junB, c-fos, and fosB, followed temporally by a gene known to be modulated by these transcription factors, i.e., transin. In situ hybridization analyses show that c-fos expression is restricted largely to neurons with condensed chromatin, a hallmark of apoptosis. As these genes are not induced in all models of apoptosis, that amylin-induced neuronal death is genetically similar to that of A beta suggests that these peptides may be neurotoxic through a common mechanism.
Tucker
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HM
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, USA.
Rydel
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Wright
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Estus
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D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D058228:Islet Amyloid Polypeptide; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger