MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging/capture in an Aβ(1-42)-induced model of Alzheimer's disease
MicroRNA-134-5p inhibition rescues long-term plasticity and synaptic tagging/capture in an Aβ(1-42)-induced model of Alzheimer's disease
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DOI：
10.1111/acel.13046
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发表时间：
2019-10-17
期刊：
影响因子：
7.8
通讯作者：
Sajikumar, Sreedharan
中科院分区：
文献类型：
--
作者：
Baby, Nimmi;Alagappan, Nithyakalyani;Sajikumar, Sreedharan
进行性记忆丧失是阿尔茨海默病（AD）最常见的特征之一，已表明它是由多种因素引起的，包括β - 淀粉样肽（Aβ）斑块的积累和神经原纤维缠结。作为记忆的细胞基础，突触可塑性和联合可塑性在AD中受损。最近的研究表明，微小RNA（miRNAs）在调节AD的可塑性变化方面具有功能相关性，因为据报道它们在许多AD脑区存在差异表达。然而，这些miRNAs在AD中的具体作用尚未阐明。我们之前曾报道，在Aβ（1 - 42）诱导的AD条件下，晚期长时程增强（晚期LTP）及其联合机制，如突触标记和捕获（STC）受损。本研究表明，一种脑特异性miRNA——miR - 134 - 5p的表达在Aβ（1 - 42）处理的AD海马体中上调。有趣的是，miR - 134 - 5p功能缺失恢复了AD中的晚期LTP和STC。在AD大脑中，抑制miR - 134 - 5p提高了可塑性相关蛋白（PRPs）、环磷腺苷效应元件结合蛋白（CREB - 1）和脑源性神经营养因子（BDNF）的表达，这些蛋白在AD条件下原本是下调的。研究结果首次证明，miR - 134介导的CREB - 1和BDNF的转录后调控是AD中可塑性缺陷的一个重要分子机制；从而表明miR - 134 - 5p作为恢复AD条件下可塑性的潜在治疗靶点具有关键作用。
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 beta peptide (A beta) 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 A beta (1-42)-induced AD condition. This study demonstrates that expression of miR-134-5p, a brain-specific miRNA is upregulated in A beta (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.