MicroRNA-195在长期脑低灌注诱发认知功能障碍中的作用及其分子机制

The Action and Molecular Mechanisms of MicroRNA-195 on Cognitive Decline Induced by Chronic Brain Hypoperfusion

长期脑低灌注(chronic brain hypoperfusion,CBH)是血管性痴呆(vascular dementia,VD)患者共有的临床特征。探讨CBH对认知功能的影响对深入理解VD的发病机制,探索临床干预策略具有重要意义。课题组通过使用双侧颈总动脉结扎(bilateral common carotid artery occlusion,BCCAO,或two-vessel occlusion,2VO)手术法构建CBH动物模型,并从miRNAs的角度系统研究了CBH对大鼠学习和记忆的影响及其分子机制。发现microRNA-195(miR-195)可以以多靶点调控的方式参与到老年痴呆的三个病理特征(β淀粉样蛋白(amyloidβpeptide,Aβ)沉积、tau蛋白过度磷酸化、神经元突触退化和神经元的死亡)的发生和发展过程中。值得关注的是,2VO引起的miR-195下调不仅可以通过上调淀粉样前体蛋白(amyloid precursor protein,APP)和β-分泌酶(β-site APP cleaving enzyme 1,BACE1)的表达从源头启动Aβ级联反应过程,并且在这个级联反应过程的每一个关键节点处为维持反应过程提供底物。该系列研究也从另外一个角度证明miRNAs可以在一个功能模块中以多靶点调控的方式参与到疾病的发生和发展过程中。

Chronic brain hypoperfusion （CBH） is a common clinical manifestation of vascular dementia （VD）. Clarifying the effects of CBH on cognitive function would help to improve our understanding the pathophysiological mechanism of VD and provide the possible therapeutic strategy for VD. In recent years, our group focused on to investigate the action and molecular mechanisms of CBH on learning and memory ability of rats using a CBH model by bilateral common carotid artery occlusion （or called two-vessel occlusion,2VO）. We found that miR-195 could regulate cognitive ability of CBH rats through targeting on varies genes simultaneously that associated with all three pathological processes including amyloid 13 peptide （A13） deposition, tau hyperphosphorylation, dendritic degeneration and neuronal loss. Importantly, miR-195 could not only prevent the initial amyloidogenic cascade response via downregulating amyloid precursor protein （APP） and 13-site APP cleaving enzyme 1 （BACE1）, but also provide sufficient requisite substrates during the amyloidogenic cascade response process. In addition, our series studies also provide evidence that miRNAs could participate in the onset and the development processes of diseases by regulating multi-targets within one functional module.