老化相关的alpha-突触核蛋白寡聚体积聚对海马神经元NMDA受体表达和功能的影响及其机制的研究

Age-related cognitive decline (ARCD) is one of the main manifestations of aging brain. Age-related alterations in the expressions and functions of NMDA receptors has been shown to be responsible for ARCD, but the underlying mechanisms remain unclear. We have previously shown that alpha-synuclein (aSyn), a protein implicated in the cognitive disorder of some neurodegenerative diseases, can regulate the expression and function of surface NMDA receptors in neuronal cells, and the levels of its oligomers increase significantly during aging. We postulate that age-related aSyn oligomer accumulation may be one of the reasons causing ARCD by affecting the expression and function of NMDA receptors. In this proposed project, we will use aging monkeys, aSyn oligomer transfected rats, and primary hippocampal neuronal cultures to study the effects of age-related aSyn oligomer accumulation on the expression and function of NMDA receptors in hippocampal neurons. We will further investigate the relations between aSyn oligomer-induced NMDA receptor alterations and NMDA receptor-mediated long term potentiation. The later is believed to be responsible for memory. The project will help understand the potential mechanisms for the cognitive disorders related to some neurodegenerative diseases.

年龄相关的认知功能下降（age-related cognitive decline, ARCD）是脑老化的主要表现，与老化引起的海马脑区NMDA受体表达和功能改变有关，但其机制不清楚。我们发现，一种与神经退行性疾病的认知功能障碍密切相关的蛋白质- - alpha-突触核蛋白（aSyn），对神经细胞膜表面NMDA受体的表达和功能具有调控作用，其寡聚体在海马脑区随年龄增长而显著升高。由此推测，老化过程中aSyn寡聚体在海马的积聚很可能通过影响NMDA受体的表达和功能引起某些与ARCD相关的记忆功能下降。本项目拟利用老化食蟹猴、aSyn寡聚体感染大鼠、培养大鼠海马神经元，研究老化相关的aSyn寡聚体积聚对海马神经元膜表面NMDA受体表达和功能的影响与机制，分析这些变化是否会进一步影响海马与记忆形成有关的长时程增强电位的形成。本项目有助于揭示与神经退行性疾病相关的认知功能障碍的机制。

年龄相关的认知功能下降（age-related cognitive decline, ARCD）是脑老化的主要表现，与老化引起的海马脑区NMDA受体表达和功能改变有关，但其机制不清楚。我们发现，一种与神经退行性疾病的认知功能障碍密切相关的蛋白质alpha-突触核蛋白（aSyn），对神经细胞膜表面NMDA受体的表达和功能具有调控作用，其寡聚体在海马脑区随年龄增长而显著升高。由此推测，老化过程中aSyn寡聚体在海马的积聚很可能通过影响NMDA受体的表达和功能引起某些与ARCD相关的记忆功能下降。本项目在前期工作的基础上利用培养大鼠海马神经元，转aSyn基因小鼠，老化食蟹猴发现aSyn水平增高可致NMDA受体NR1亚基下膜，Ca2+内向电流减少，并且伴随Rab5B水平增高。当敲减Rab5B蛋白后，则显著缓解aSyn致Ca2+内向电流的减低，提示，Rab5B介导了aSyn水平增高引起的NR1内在化及Ca2+减低。我们进一步利用老化人脑发现，aSyn寡聚体在海马和纹状体部位呈增龄性增加。并且在这两部位的NR1下膜也呈增龄性增加的趋势，提示aSyn寡聚体更加显著促进人脑中NR1的内在化作用。这些变化会进一步影响海马与记忆形成有关的长时程增强电位的形成。本项目有助于揭示与神经退行性疾病相关的认知功能障碍的机制。