title: MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer's disease.
abstract: The contribution of mutations in amyloid precursor protein (APP) and presenilin (PSEN) to familial Alzheimer's disease (AD) is well established. However, little is known about the molecular mechanisms leading to amyloid β (Aβ) generation in sporadic AD. Increased brain ceramide levels have been associated with sporadic AD, and are a suggested risk factor. Serine palmitoyltransferase (SPT) is the first rate-limiting enzyme in the de novo ceramide synthesis. However, the regulation of SPT is not yet understood. Evidence suggests that it may be posttranscriptionally regulated. Therefore, we investigated the role of miRNAs in the regulation of SPT and amyloid β (Aβ) generation. We show that SPT is upregulated in a subgroup of sporadic AD patient brains. This is further confirmed in mouse model studies of risk factors associated with AD. We identified that the loss of miR-137, -181c, -9, and 29a/b-1 increases SPT and in turn Aβ levels, and provides a mechanism for the elevated risk of AD associated with age, high-saturated-fat diet, and gender. Finally, these results suggest SPT and the respective miRNAs may be potential therapeutic targets for sporadic AD.
authors: Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.
authors: Hirosha
authors: H
authors: Geekiyanage
authors: Christina
authors: C
authors: Chan
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D011180:Postmortem Changes; D051381:Rats; D017207:Rats, Sprague-Dawley; D051102:Serine C-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D013109:Sphingomyelins / Q000378:metabolism; D013223:Statistics as Topic; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002518:Ceramides; C545567:MIRN137 microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D013109:Sphingomyelins; C487784:SPTLC1 protein, human; C495089:SPTLC2 protein, human; D051102:Serine C-Palmitoyltransferase