ADDLs 对谷氨酸受体跨膜转运及突触可塑性影响

It is widely accepted that ADDLs (Aβ-derived diffusible ligands) play a prominent role in triggering the early cognitive deficits that constitute Alzhimer's Disease (AD).However, the mechanisms for its effects on synaptic plasticity are not fully understood. So targeting glutamate receptors (GluRs) trafficking and its regulation is a new strategy for AD early treatment. Based on the previous studies on Aβ excitoxicity and molecular mechanisms as well as several year researches on synaptic plasticity of psychiatric disorders, we will clarify the effects and molecular mechanisms of ADDLs on trafficking of specific subunits of GluRs (GluA1, GluN1/2B) and synaptic plasticity with both in vivo and in vitro experiments. Elucidating the molecular mechanisms that ADDLs affect GluRs surface expression and disrupt synaptic plasticity for triggerring memory malfunction and cognitive deficits will provide new strategy for early treatment of AD and shed light on new target for drug discovery.

ADDLs（Aβ-derived diffusible ligands）作为老年痴呆疾病（AD）发病的关键分子在早期认知功能障碍方面的作用日益受到重视，但是其对突触可塑性的影响机制并不是很清楚，因而靶向于谷氨酸受体（glutamate receptors, GluRs）跨膜转运及其调控成为寻求AD早期治疗的新策略。基于申请者以往研究Aβ的神经毒性及其分子机制的基础，结合多年对神经精神疾病突触可塑性的研究经验，在整体、细胞和分子水平阐明ADDLs 对GluRs特定亚基（GluA1, GluN1/2B）跨膜转运的影响及突触可塑性变化的分子机制，着力阐述ADDLs 影响GluRs在突触膜表面表达干扰突触可塑性形成导致记忆和认知功能障碍的分子机制，为AD 的发病及早期治疗提供理论依据并为研发理想的治疗药物提供新的靶标。

可溶性Aβ寡聚体，即ADDLs （Aβ-derived diffusible ligands）作为阿尔茨海默病（AD）发病的关键分子在突触可塑性改变和随后的记忆功能损伤及认知功能障碍方面的作用日益受到重视。ADDLs通过影响突触功能导致和AD相关的认知功能损伤。兴奋性突触传递和突触表面AMPA受体（AMPAR）的数量和激活紧密相连，而NMDA受体（NMDAR）在诸如长时程增强（long-term potentiation, LTP）、长时程抑制（long-term depression, LTD）等突触可塑性事件中发挥中心作用；另一方面细胞表面AMPAR定位和NMDAR活性密切相关。因而靶向于谷氨酸受体（glutamate receptors, GluRs）跨膜转运及其调控成为寻求AD治疗的新策略。. 本项目阐明了ADDLs影响GluRs 跨膜转运的机制，揭示了ADDLs降低GluA1、GluN1/2B在细胞膜表面表达、抑制LTP产生的分子机制；左旋千金藤啶碱L-SPD通过D1/PKA信号通路促进AMPA受体跨膜转运及突触可塑性从而改善APP小鼠学习记忆；ADDLs通过激活突触外膜上NMDA受体，影响NMDA受体跨膜转运及APP小鼠学习记忆；设计筛选的干扰ADDLs和EphB2结合小肽Pep63有助于改善NMDA受体跨膜转运并改善APP小鼠学习记忆。本研究拓宽了研究AD疾病的新思路，为靶向于GluRs跨膜转运及其调控提供AD治疗的新策略和药物作用的靶点。