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Abstract：
Progressive memory loss is one of the most common characteristics of Alzheimer\'s disease (AD), which has been shown to be caused by several factors including accumulation of amyloid β peptide (Aβ) plaques and neurofibrillary tangles. Synaptic plasticity and associative plasticity, the cellular basis of memory, are impaired in AD. Recent studies suggest a functional relevance of microRNAs (miRNAs) in regulating plasticity changes in AD, as their differential expressions were reported in many AD brain regions. However, the specific role of these miRNAs in AD has not been elucidated. We have reported earlier that late long-term potentiation (late LTP) and its associative mechanisms such as synaptic tagging and capture (STC) were impaired in Aβ (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in Aβ (1-42)-treated AD hippocampus. Interestingly, the loss of function of miR-134-5p restored late LTP and STC in AD. In AD brains, inhibition of miR-134-5p elevated the expression of plasticity-related proteins (PRPs), cAMP-response-element binding protein (CREB-1) and brain-derived neurotrophic factor (BDNF), which are otherwise downregulated in AD condition. The results provide the first evidence that the miR-134-mediated post-transcriptional regulation of CREB-1 and BDNF is an important molecular mechanism underlying the plasticity deficit in AD; thus demonstrating the critical role of miR-134-5p as a potential therapeutic target for restoring plasticity in AD condition.
摘要：
进行性记忆丧失是阿尔茨海默病（AD）最常见的特征之一，已被证明是由多种因素引起的，包括淀粉样β肽（Aβ）斑块和神经原纤维缠结的积累。突触可塑性和缔合可塑性，记忆的细胞基础，在AD中受损。最近的研究表明microRNAs（miRNAs）在调节AD可塑性变化中的功能相关性，因为它们的差异表达在许多AD脑区被报道。然而,这些miRNA在AD中的具体作用尚未阐明。我们早些时候报道过，在Aβ（1-42）诱导的AD条件下，晚期长期增强（LTP）及其相关机制（例如突触标记和捕获（STC））受损。这项研究表明，miR-134-5p的表达，脑特异性miRNA在Aβ(1-42)处理的AD海马中上调。有趣的是,miR-134-5p功能的丧失恢复了AD晚期LTP和STC。在AD大脑中，抑制miR-134-5p升高可塑性相关蛋白（PRPs）的表达，cAMP反应元件结合蛋白（CREB-1）和脑源性神经营养因子（BDNF），否则在AD条件下下调。结果提供了第一个证据，即miR-134介导的CREB-1和BDNF的转录后调控是AD可塑性缺陷的重要分子机制;因此证明了miR-134-5p作为恢复AD条件可塑性的潜在治疗靶标的关键作用。
