MicroRNA-137/181c Regulates Serine Palmitoyltransferase and In Turn Amyloid β, Novel Targets in Sporadic Alzheimer's Disease
Open accessAbstract
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.
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Inhibition of miRNAs that regulate SPTLC increases SPTLC levels, leading to more Aβ production.
“Conversely, inhibition of those miRNAs increased SPTLC levels, leading to more Aβ production.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [112]
Overexpression of miR-9 and miR-29a/b-1 decreases levels of SPTLC2 and ceramide.
“overexpression of miR-9 and miR-29a/b-1 decreased the levels of SPTLC2 and ceramide [112].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [112]
Levels of miRNAs regulating SPTLC1 and SPTLC2 are negatively correlated with SPTLC1 and SPTLC2 levels in sporadic AD brains.
“the levels of those miRNAs were negatively correlated with the levels of SPTLC1 and SPTLC2 in sporadic AD brains.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [112]
miR-137 and miR-181c decrease levels of SPTLC1 and ceramide in primary astrocytes.
“They found that miR-137 and miR-181c decrease the levels of SPTLC1 and ceramide in primary astrocytes.”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [112]
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- Authors
- Geekiyanage, H., & Chan, C.
- Affiliations
- Michigan State University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-10-12
- Volume
- 31
- Issue
- 41
- Pages
- 14820-14830
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3200297
- OpenAlex
- W2055103272
- Cited by
- 254
- References
- 61
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 15 · 2023: 15 · 2022: 12 · 2021: 16 · 2020: 10 · 2019: 25 · 2018: 14 · 2017: 22 · 2016: 18 · 2015: 20 · 2014: 31 · 2013: 28 · 2012: 11
- FWCI
- 15.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0941055, 1049127)
- Michigan State University
- College of Engineering, Michigan State University
- National Institute on Aging (P30AG028383)
- National Institute of General Medical Sciences (R01GM079688, R01GM089866)
- National Center for Research Resources (R21RR024439)
- Division of Chemical, Bioengineering, Environmental, and Transport Systems (0941055)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- sporadic Alzheimer's disease, serine palmitoyltransferase, amyloid-beta production, microRNA-137, miR-9, ceramide synthesis, post-transcriptional regulation, high saturated fat diet, age, sex differences, therapeutic target
- MeSH terms
- Age Factors, Aged, 80 and over, Alzheimer Disease, Animals, Animals, Newborn, Astrocytes, Brain, Cells, Cultured, Ceramides, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Postmortem Changes, Sex Factors, Sphingomyelins, Statistics as Topic, Transfection, Gene Expression Regulation, Enzymologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Rats, Sprague-Dawley, Gene Expression Regulation, Developmental, MicroRNAs, Serine C-Palmitoyltransferase, Mice, Rats, Diet, High-Fat
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