Involvement of Paired Immunoglobulin-like Receptor B in Diabetes-Associated Cognitive Dysfunction Through Modulation of Axon Outgrowth and Dendritic Remodeling
Involvement of Paired Immunoglobulin-like Receptor B in Diabetes-Associated Cognitive Dysfunction Through Modulation of Axon Outgrowth and Dendritic Remodeling
复制标题
配对免疫球蛋白样受体 B 通过调节轴突生长和树突重塑参与糖尿病相关认知功能障碍
DOI：
10.1007/s12035-021-02679-1
复制
发表时间：
2022-01-29
影响因子：
5.1
通讯作者：
Wang, Qiang
中科院分区：
文献类型：
--
作者：
Pu, Kairui;Wu, Meiyan;Wang, Qiang
2型糖尿病患者具有发生认知功能障碍的高风险，其中神经结构可塑性起着关键作用。成对免疫球蛋白样受体B（PirB）是一种主要在神经元中表达的受体，是神经突起生长和神经可塑性的重要抑制剂。然而，PirB在2型糖尿病相关认知功能障碍中的作用仍然未知。本研究通过Morris水迷宫实验观察24周龄db/db小鼠学习记忆障碍，透射电镜观察发现db/db小鼠海马内突触数量沿着突触后密度的长度减少。此外，使用蛋白质印迹和免疫荧光分析，db/db小鼠海马中的PirB表达显著上调。在培养的海马神经元中，高葡萄糖处理减少了最长的神经突以及轴突起始段（AIS）的长度，而沉默PirB表达挽救了高葡萄糖诱导的神经突生长抑制，但不是AIS。此外，当通过腺相关病毒注射进行PirB敲低时，db/db小鼠中的认知缺陷、树突形态缺陷和突触相关蛋白损失得到缓解。总之，PirB通过调节轴突生长和树突重塑参与糖尿病相关的认知功能障碍，为糖尿病相关的认知功能障碍提供了潜在的治疗靶点。
Type 2 diabetic patients have high risk of developing cognitive dysfunction, in which neural structural plasticity has played a pivotal role. Paired immunoglobulin-like receptor B (PirB), a receptor mainly expressed in neurons, acts as a critical inhibitor of neurite outgrowth and neural plasticity. However, the role of PirB in type 2 diabetes-associated cognitive dysfunction remains unknown. In this study, learning and memory impairment was observed in 24-week-old db/db mice by performing Morris water maze task, and the number of synapses along with the length of postsynaptic density by transmission electron microscopy were reduced in the hippocampus of db/db mice. Furthermore, PirB expression in the hippocampus of db/db mice was significantly upregulated using western blotting and immunofluorescence analysis. In cultured hippocampal neurons, high glucose treatment reduced the length of the longest neurite as well as axon initial segment (AIS), whereas silencing PirB expression rescued high glucose-induced neurite outgrowth inhibition, but not AIS. Additionally, cognitive deficits, dendrite morphology defects, and synapse-related proteins loss in db/db mice were alleviated when PirB knockdown was performed by adeno-associated virus injection. In conclusion, PirB is involved in diabetes-associated cognitive dysfunction through modulation of axon outgrowth and dendritic remodeling, providing a potential therapeutic target for diabetes-associated cognitive dysfunction.