miR-125a调控阿尔茨海默病认知功能及其机制研究

Alzheimer’s disease (AD) is the most prevalent form of dementia, and synaptic plasticity impairment is one of the early pathogenetic features of AD. In the preliminary study, we found that microRNA-125a (miR-125a) was significantly decreased in the cerebral cortex, hippocampus and serum of APP/PS1 mice. In this proposed study, we will mainly focus on the following three specific aims: 1) to confirm that miR-125a protects the synaptic plasticity and attenuates memory deficits in APP/PS1 mice; 2) to verify that α/β-hydrolase domain 6 (Abhd6) is a downstream target of miR-125a and is involved in the regulation of synaptic plasticity and memory processing in APP/PS1 mice; and 3) to identify the correlation of miR-125a in the serum and cerebral spinal fluid (CSF) and the memory deficits in the AD patients. These results will suggest that miR-125a modulates the synaptic plasticity and AD neuropathology. We are the first to investigate the role of miR-125a/Abhd6 in the synaptic dysfunction and memory deficits of AD, showing that miR-125a/Abhd6 is a potential therapeutic target and prognosis factor in AD patients.

阿尔茨海默病（Alzheimer’s disease，AD）是临床最常见的老年痴呆类型，突触可塑性受损是AD早期病理改变之一。我们前期研究发现APP/PS1转基因小鼠皮层、海马和血清中miR-125a表达显著下调，提示miR-125a可能参与了突触可塑性和认知功能的调控。本课题利用行为学、神经电生理、病理学、免疫学及分子生物学等技术进行以下体内外研究：1）明确miR-125a对APP/PS1小鼠突触可塑性及认知功能的影响；2）证实Abhd6是miR-125a下游靶基因，研究miR-125a是否通过Abhd6调控APP/PS1小鼠认知功能；3）探讨AD患者血清及脑脊液miR-125a水平与认知功能的相关性。本项目首次研究miR-125a/Abhd6对于AD突触可塑性及认知功能的调控，提示miR-125a可能是AD的潜在治疗靶点，对阐明AD的病理机制有一定贡献，为临床诊断及治疗AD提供依据。

阿尔茨海默病（Alzheimer's disease，AD）是临床最常见的老年痴呆类型，目前发病机制尚不清楚。突触可塑性受损是AD早期病理改变之一，研究报道miRNA参与了AD突触可塑性与认知功能障碍。通过本项目的研究，我们发现：1）与同月龄野生型小鼠相比，APP/PS1转基因小鼠海马miRNA表达谱存在显著差异，17个miRNA表达上调，47个miRNA表达下调，其中miR-125a下调约40%；2）过表达miR-125a能够改善APP/PS1小鼠的突触功能和学习记忆能力，而抑制miR-125a加重APP/PS1小鼠的突触功能和学习记忆障碍；3）过表达miR-125a减少Aβ的沉积，可能与上调ADAM10有关；4）α/β水解酶结构域-6（alpha/beta-hydrolase domain 6, Abhd6）是miR-125a的靶基因，使用Abhd6抑制剂（WWL70）或者干扰RNA均能够改善APP/PS1小鼠的突触传递和学习记忆功能；5）Abhd6能够逆转过表达miR-125a对AD的保护作用；6）miR-125a在aMCI和AD患者血清表达显著下调，而脑脊液表达无明显差异，且2-AG在血清和脑脊液表达均无显著差异，提示血清miR-125a可能作为AD早期诊断的分子标志物。