CaSR在阿尔茨海默病认知功能障碍中的作用及机制研究

Soluble amyloid-β peptide (Aβ) oligomers are the major toxic species responsible for development and progression of congitive impairments in Alzheimer's disease (AD). Calcium sensing receptor (CaSR) can be activated by soluble Aβ. However the role and underlying mechanism of CaSR in Aβ mediated cognitive defects is unclear. Our preliminary data indicated that CaSR expression was increased both in soluble Aβ42 treated cultured hippocampal neurons and hippocampal silces from AD transgenic mice. Furthermore, CaSR antagonist NPS 2143 prevented the spine loss in soluble Aβ treated hippocampal neurons and recognition memory defects in AD animal model. Thus, overactivation of CaSR mediated the congnitive impairments of AD. In this project, we will combine molecular technology, live-cell imaging and electrophysiology with behavior methods to investigate the underlying signal pathways of CaSR in soluble Aβ oligomer mediated synaptic formation, synaptic plasticity and cognition defects. Thus, we will indicate the role and mechanism of CaSR medicated cognitive defects in AD through different levels study including using cell, tissue, and animal. The knowledge from this study will pave the way for the clinical treatment of AD through CaSR and its downstream signaling pathways.

可溶性的Aβ寡聚体是介导阿尔茨海默病(Alzheimer’s disease, AD)记忆功能障碍的重要致病因子。钙敏感受体(calcium sensing receptor, CaSR)在神经末梢分布并可以被可溶性Aβ激活。然而，CaSR在Aβ介导的认知功能障碍中的作用和机制尚不清楚。我们前期的研究表明AD转基因鼠海马中CaSR表达量显著增加，CaSR拮抗剂能显著改善AD模型动物中辨别记忆损伤。因此，本项目采用活细胞成像、电生理、行为学等技术，阐明CaSR在可溶性Aβ寡聚体引起的海马神经元突触形成、突触可塑性以及认知功能障碍中的作用及下游的信号通路，评估干预CaSR及下游信号通路对逆转和延缓AD认知功能障碍的意义。为AD预防和治疗新策略提供理论依据。

项目组圆满完成各项任务及指标。课题研究期间在Journal of Alzheimer’s disease、metabolic brain disease等杂志发表本基金资助SCI论文3篇，核心期刊一篇，该基金是所有论文的第一标注基金。在本项目中行为学和分子生物学技术用于研究CaSR在AD模型鼠认知功能障碍中的作用。活细胞成像和免疫细胞化学的方法用于研究CaSR在Aβ介导海马神经元突触形成缺陷中的作用及机制。研究发现CaSR拮抗剂NPS2143处理能以浓度依赖性方式防止Aβ1-42寡聚体诱导的小鼠工作记忆和空间学习记忆缺陷。用NPS2143抑制CaSR活性，或用CaSR-shRNA降低CaSR表达都能预防可溶性Aβ1-42寡聚体诱导的树突丝和突触损伤。Aβ1-42处理增加了海马神经元和海马组织内cPLA2和PGE2的含量。抑制CaSR活性或降低CaSR表达能逆转Aβ1-42介导的cPLA2和PGE2含量的增加。我们的结果提示CaSR参与可溶性Aβ介导的突触损伤和认知功能缺陷。CaSR介导的损伤部分是通过激活cPLA2/PGE2通路。该研究为CaSR作为AD治疗干预靶点提供了理论依据。