Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression
Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression
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DOI：
10.1073/pnas.0710263105
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发表时间：
2008-04-29
影响因子：
11.1
通讯作者：
De Strooper, Bart
中科院分区：
文献类型：
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作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
虽然APP和PSEN基因在遗传性阿尔茨海默病(AD)病例中的作用已被证实，但对散发性AD中影响Aβ生成的分子机制知之甚少。Aβ清除不足当然是一种可能性，但APP或BACE1/β-分泌酶等蛋白质的表达增加也可能与疾病有关。因此，我们研究了散发性AD患者microRNA(MiRNA)表达谱的变化，发现几个可能参与APP和BACE1表达调控的miRNAs在疾病脑中似乎减少。我们发现miR-29a、-29b-1和-9在体外可以调节BACE1的表达。在表现出异常高BACE1蛋白的AD患者中，miR-29a/b-1簇显著减少(并且是AD痴呆的特异性)。在大脑发育和原代神经元培养中，该簇和BACE1的表达之间也发现了类似的相关性。最后，我们在细胞培养模型中提供了miR-29a/b-1表达和Aβ生成之间潜在因果关系的证据。我们认为，特定miRNAs的丢失可能导致散发性AD患者BACE1和Aβ水平的升高。
Although the role of APP and PSEN genes in genetic Alzheimer's disease (AD) cases is well established, fairly little is known about the molecular mechanisms affecting A beta generation in sporadic AD. Deficiency in A beta clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/beta-secretase may also be associated with the disease. We therefore investigated changes in microRNA (miRNA) expression profiles of sporadic AD patients and found that several miRNAs potentially involved in the regulation of APP and BACE1 expression appeared to be decreased in diseased brain. We show here that miR-29a, -29b-1, and -9 can regulate BACE1 expression in vitro. The miR-29a/b-1 cluster was significantly (and AD-dementia-specific) decreased in AD patients displaying abnormally high BACE1 protein. Similar correlations between expression of this cluster and BACE1 were found during brain development and in primary neuronal cultures. Finally, we provide evidence for a potential causal relationship between miR-29a/b-1 expression and A beta generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and A beta levels in sporadic AD.