Journal
JOURNAL OF NEUROSCIENCE
Volume 31, Issue 41, Pages 14820-14830Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3883-11.2011
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Funding
- National Institute of Health [R01GM079688, R01GM089866, R21RR024439]
- National Science Foundation [CBET 0941055, CBET-1049127]
- Michigan State University (MSU) Foundation
- MSU
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [1049127] Funding Source: National Science Foundation
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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 beta (A beta) 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 beta (A beta) 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 A beta 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.
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