MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer's disease.
MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer's disease.
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DOI：
10.1523/jneurosci.3883-11.2011
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发表时间：
2011-10-12
期刊：
影响因子：
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通讯作者：
Chan C
中科院分区：
文献类型：
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作者：
Geekiyanage H;Chan C
淀粉样前体蛋白（APP）和早老素（PSEN）突变对家族性阿尔茨海默病（AD）的作用已得到充分证实。然而，关于导致散发性AD中淀粉样蛋白β（Aβ）产生的分子机制知之甚少。脑神经酰胺水平升高与散发性AD相关，是一种建议的风险因素。丝氨酸棕榈酰转移酶（SPT）是神经酰胺从头合成的第一限速酶。然而，对防止酷刑小组委员会的监管尚不清楚。有证据表明，它可能是转录后调节。因此，我们研究了miRNAs在SPT和淀粉样蛋白β（Aβ）生成的调节中的作用。我们发现丝氨酸棕榈酰转移酶（SPT）在散发性AD患者脑中的一个亚组中上调。这在与AD相关的风险因素的小鼠模型研究中得到进一步证实。我们发现，miR-137、-181 c、-9和29 a/B-1的缺失增加了SPT，进而增加了Aβ水平，并提供了与年龄、高饱和脂肪饮食和性别相关的AD风险升高的机制。最后，这些结果表明SPT和相应的miRNAs可能是散发性AD的潜在治疗靶点。
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 (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 post-transcriptionally regulated. Therefore, we investigated the role of miRNAs in the regulation of SPT and amyloid beta (Aβ) generation. We show that serine palmitoyltransferase (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.