MicroRNA-137/181c Regulates Serine Palmitoyltransferase and In Turn Amyloid β, 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: 6.75). 10/2011; 31(41):14820-30. DOI: 10.1523/JNEUROSCI.3883-11.2011
Source: PubMed

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.

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    • "Evidence in the literature support that inhibiting de novo ceramide synthesis decreases the A␤ production and adding ceramide exogenously increases A␤ production (Patil et al., 2007; Puglielli et al., 2003). More recently, we showed that ceramide and SPT expression levels are elevated in a subgroup of sporadic AD patients (Geekiyanage and Chan, 2011). In this study we demonstrate how increased levels of ceramides in the astrocytes upon culture with PA leads to the upregulation of BACE1 in the primary neurons, mediated by the SMases-ceramide pathway. "
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    ABSTRACT: Astrocytes play a critical role in neurodegenerative diseases, including Alzheimer's disease (AD). Previously, we showed that saturated free fatty acid, palmitic acid (PA), upregulates β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) level and amyloidogenesis in primary rat neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from PA-treated astrocytes upregulates BACE1 level in neurons are unknown. This study demonstrates that serine palmitoyltransferase (SPT) in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (SMase) in the neurons, to propagate the deleterious effects of PA (i.e., BACE1 upregulation). In support of the relevance of SPT in AD, our laboratory recently measured and found SPT levels to be significantly upregulated in AD brains as compared with controls. Cytokines, namely tumor necrosis factor-α and interleukin-1β, released into the conditioned media of PA-treated astrocytes activate neural and acidic SMase in the neurons. Neutralizing the cytokines in the PA-treated astrocyte conditioned media reduced BACE1 upregulation. However, inhibiting SPT in the astrocytes decreased the levels of both tumor necrosis factor-α and interleukin-1β in the conditioned media, which in turn reduced the SMase activities and BACE1 level in primary neurons. Thus, our results suggest that the activation of the astrocytes by PA is mediated by SPT, and the activated astrocytes increases BACE1 level in the neurons; the latter is mediate by the SMases.
    Neurobiology of aging 06/2012; 34(2). DOI:10.1016/j.neurobiolaging.2012.05.017 · 4.85 Impact Factor
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    • "Moreover, screening for miRNAs in the sera as biomarkers , that i) directly affect a fundamental feature of AD neuropathology , ii) are diagnostically sensitive enough to detect, iii) can detect AD early in the course of the disease progression, and iv) are non-invasive, simple to perform and inexpensive, make them potentially good diagnostic biomarkers in accordance with the criteria described by the National Institute on Aging (1998). In a previous study (Geekiyanage and Chan, 2011) we identified that a subgroup of AD patients display increased levels of ceramide along with increased SPTLC1/2 protein levels in neocortices. However, the SPTLC1/2 mRNA levels did not differ from their control counterparts. "
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    ABSTRACT: There is an urgent need to identify non-invasive biomarkers for the detection of sporadic Alzheimer's disease (AD). We previously studied microRNAs (miRNAs) in AD autopsy brain samples and reported a connection between miR-137, -181c, -9, -29a/b and AD, through the regulation of ceramides. In this study, the potential role of these miRNAs as diagnostic markers for AD was investigated. We identified that these miRNAs were down-regulated in the blood serum of probable AD patients. The levels of these miRNAs were also reduced in the serum of AD risk factor models. Although the ability of these miRNAs to conclusively diagnose for AD is currently unknown, our findings suggest a potential use for circulating miRNAs, along with other markers, as non-invasive and relatively inexpensive biomarkers for the early diagnosis of AD, however, with further research and validation.
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    ABSTRACT: Alzheimer's disease (AD) is a complex neurodegenerative disorder and is the most common form of dementia in the elderly. Accumulating evidence in AD research suggests that alterations in the microRNA (miRNA) network could contribute to risk for the disease. miRNAs are conserved small non-coding RNAs that control gene expression at the posttranscriptional level and are essential for neuronal function and survival. The results from recent profiling experiments in humans suggest that a number of specific miRNAs are misregulated in disease conditions, several of which have been implicated in the regulation of key genes involved in AD, including APP, BACE1 and MAPT. Moreover, rare disease-specific polymorphisms have been identified in known and putative miRNA target sites located within the 3'untranslated regions (3'UTRs) of APP and BACE1 genes. Here, we review current findings regarding miRNA research in humans and various cellular and animal models to provide a strong basis for future research aimed at understanding the potential contribution of miRNAs to AD pathophysiology.
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