MicroRNA-137/181c Regulates Serine Palmitoyltransferase and In Turn Amyloid , Novel Targets in Sporadic Alzheimer's Disease

Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2011; 31(41):14820-30. DOI: 10.1523/JNEUROSCI.3883-11.2011
Source: PubMed


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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    • "miR-137 is likely a central factor coordinating the timing and expression of multiple schizophrenia risk genes, especially those related to neuronal differentiation and proliferation [2, 8, 10, 24, 31, 32]. Thus, we suspect that dysregulation of miR-137 expression and the subsequent abnormal expression of miR-137 target genes contribute to the neurodevelopment, disease progression, and neuromorphological pathologies present in schizophrenia [33]. "
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    • "The mRNA levels of hnRNPA1 were observed to be negatively correlated with miR-590-3p levels, supporting the hypothesis that this miRNA acts as a regulator of hnRNPA1, therefore influencing APP production (Villa et al., 2011). Another study on candidate miRNAs, previously found to be reduced in post-mortem brain cortices of AD patients (Geekiyanage and Chan, 2011), described a downregulation of 4 of these (among them, miR 29a/b) in the serum of individuals suffering from mild cognitive impairment (MCI) or AD (Geekiyanage et al., 2012). This consistency of results indicates that peripheral blood and its derivatives represent valid tissues to study miRNAs in CNS diseases, as they could reflect brain alterations. "
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    • "Geekiyanage et al. (2012) compared concentrations of five miRNA, namely miR-137, miR-181c, miR-9, miR-29a, and miR-29b in serum of MCI and AD patients with their levels in serum of age-matched controls. The choice of miRNA was based on the previous study (Geekiyanage and Chan, 2011) that demonstrated their involvement in AD pathogenesis and downregulation of these miRNA in the brain cortex of sporadic AD patients. Using RT-PCR and normalization per spiked cel-miR-39 and internal miR-22, miR-191, and miR-126 the authors demonstrated that the levels of miR-137, miR-181c, miR-9, miR-29a, and miR-29b are significantly lower in serum of MCI and AD patients, compared to controls. "
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