HIP1R在阿尔茨海默病突触功能损害导致的认知障碍中的作用及机制研究

Alzheimer’s disease (AD), is the leading cause of dementia in the elderly. Accumulative evidence has shown that hippocampal dendritic spine loss and altered synaptic plasticity play a major role in AD-associated cognitive deficits. However, the underlying mechanism is unclear. Our previous study revealed that the expression of huntingtin interacting protein 1 related protein (HIP1R) was decreased in AD model cells and brains of AD model mice. We also found HIP1R can regulate spine density, size and excitatory synaptic transmission in cultured hippocampal neurons. In addition, we acquired similar spine changes by disturbing the interaction of HIP1R with cortical actin binding protein (Cortactin). These results suggest that HIP1R may be important for synaptic function and cognitive function through its interaction with Cortactin in AD. This project aims to examine the potential role of HIP1R in regulating the synaptic structure and function, and evaluate the protective effect of HIP1R on cognitive function in AD. Furthermore, we intend to explore the mechanism of HIP1R’s protective effects on AD-associated synaptic dysfunction and cognitive deficits. It would improve our understanding of the pathogenesis of AD and provide potential therapeutic targets for AD treatment.

阿尔茨海默病(AD)是导致老年痴呆的主要原因，海马神经元的突触缺失及突触可塑性变化在AD导致的认知功能障碍中发挥重要作用，但具体机制尚不清楚。本课题组发现，在AD模型细胞及动物中亨廷顿相互作用蛋白1相关蛋白（HIP1R）表达显著降低；而HIP1R表达降低会导致培养的海马神经元树突棘数目减少、体积减小，兴奋性突触功能受到抑制；另外，干扰HIP1R与皮层蛋白（Cortactin）的相互作用能够得到与敲减HIP1R相似的结果。提示在AD中，HIP1R可能通过与Cortactin相互作用调节突触数目、结构及功能，进而影响认知功能。本项目拟用病毒注射、电生理记录及行为学检测等方法，在相关模型鼠中，研究HIP1R如何调节海马神经元的突触数目、结构及功能，证明在AD中HIP1R对认知功能的保护作用，探索并初步明确HIP1R在AD中的作用机制，为研究AD发病机制、预防及治疗提供新的理论思路和药物靶点。

我们的前期研究发现，在培养的海马神经元中亨廷顿相互作用蛋白1相关蛋白（HIP1R）能够影响神经元的发育及兴奋性突触的功能，通过构建HIP1R条件性敲除鼠及过表达鼠，我们证明了脑内缺失或降低HIP1R表达会影响小鼠的学习记忆能力，导致小鼠神经元兴奋性谷氨酸受体的表达降低；相反，增加HIP1R的蛋白表达，会增加树突棘的密度，增强兴奋性谷氨酸受体的表达；在AD患者及AD模型小鼠的脑组织中，HIP1R 表达呈降低趋势，在过表达了HIP1R的阿尔茨海默病（AD）模型鼠中，APP的表达显著降低，并且淀粉样斑块的形成显著减少。以上结果证明HIP1R在小鼠的学习记忆过程中发挥了关键作用，并且过表达HIP1R能够挽救AD所产生的不良现象，我们的研究结果将有助于更好的了解阿尔茨海默病的发病机制，并有望为阿尔茨海默病研究提供新的线索及治疗手段。