mPFC星形胶质细胞Tenascin C介导AD空间记忆损伤的作用与机制

老龄化与老年病已成为全球问题，空间记忆损伤是阿尔兹海默病（Alzheimer’s Disease, AD）的主要临床表征。我们的前期结果发现胞外基质Tenascin C（TNC）-星形胶质细胞与AD发生密切相关。基于AD早期发生的星形胶质细胞激活迁变、胞外基质网络重构的新视角，本项目拟利用分子生物学、动物行为、电生理、光遗传等技术，聚焦Aβ病理与AD空间记忆损伤，验明硫酸软骨蛋白聚糖水解酶ChABC抗AD的Aβ病理机制，明确胞外基质TNC-星形胶质细胞-Aβ与空间记忆的相关性，解析mPFC TNC调控Aβ生成和聚集的细胞分子机制。构建AD发生中星形胶质细胞激活迁变，TNC与Aβ合成/聚集、解聚/清除的新途径，以丰富神经退行性疾病的星形胶质细胞-胞外基质的新理解，为胞外基质网络重构与Aβ发生的AD诊疗与药物研发提供新的科学和实践依据。

Aging and senile diseases have become global problems. Spatial memory impairment is one of the main clinical manifestations of Alzheimer's disease (AD). Our previous results indicated that the extracellular matrix Tenascin C (TNC)-astrocytes are closely associated with the occurrence of AD. Based on the activation and transition of astrocytes and the remodeling of extracellular matrix network in the early stage of AD, this project focus on amyloid-β (Aβ) pathology and the impairment of spatial memory. We will be detected the Aβ pathological mechanism of chondroitin sulfate proteoglycan hydrolase ChABC against AD. Therefore, the correlation between TNC-astrocytes-Aβ and spatial memory impairment will be unveiled. We are going to explore the cellular and molecular mechanism of the mPFC TNC regulating the production and aggregation of Aβ. Overall, this project will construct new pathways for the activation and migration of astrocytes, the synthesis/ aggregation, depolymerization/clearance of Aβ and TNC in AD’s physiopathology proceeding. It enriched the new understanding of astrocyte-extracellular matrix of neurodegenerative diseases, and provided a new insight for the diagnosis, treatment and drug discovery of AD characterized by Aβ occurrence and extracellular matrix network reconstruction.