TDP-43在阿尔茨海默病和慢性创伤性脑病tau病理中的作用和分子机制

Abnormally hyperphosphorylated tau aggregated into neurofibrillary tangles in neurons is a common pathological feature for Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). TDP-43 aggregated inclusion has been observed in two third of AD and 85% CTE brain, suggesting a potential underlying linkage between the two. TDP-43 is a DNA/RNA binding protein and regulates the processing of mRNA. In the preliminary study, we found that TDP-43 regulated tau expression and the alternative splicing of tau exon 10, two key events involved in the pathogenesis. TDP-43 inhibited tau mRNA stability and enhanced tau mRNA degradation, leading to a decrease in tau expression. TDP-43 promoted tau exon 10 inclusion, resulting in an increased 4R-tau expression. In AD brain, TDP-43 level was decreased and correlated with total tau level and 3R-tau level negatively. Thus, we hypothesized that TDP-43 may contribute to tau pathology in AD and CTE through regulation of tau mRNA stability and tau exon 10 splicing. To test this hypothesis, we proposed 1) to study the regulation of tau mRNA stability and tau expression by TDP-43, 2) to investigate the regulation of the alternative splicing of tau exon 10 by TDP-43, 3) to determine the role of TDP-43 in tau pathogenesis in vivo, and 4) to evaluate the role of TDP-43 in tau pathologies in traumatic brain injury. In the present project, we will study the molecular mechanism of TDP-43 involved in the tau pathogenesis in AD and CTE, which will provide molecular basis for the prevention and treatment of AD and CTE and related neurodegenerative diseases.

tau病理是阿尔茨海默病(AD)和慢性创伤性脑病(CTE)的共同病理特征，2/3的AD和85%的CTE伴有TDP-43病理，但是tau与TDP-43的关系不明。我们预实验发现TDP-43抑制tau mRNA稳定性并促进tau外显子10编码。因此，TDP-43可能通过调节tau表达和tau外显子10的可变剪接，在tau病理发生发展及AD和CTE致病中起重要作用。本项目拟探讨：1)TDP-43对tau mRNA稳定性调节机制；2)TDP-43对tau外显子10可变剪接调节机制；3)TDP-43在体内对tau病理的影响；4)TDP-43在脑创伤所致tau病理中的作用。从分子、细胞、动物等多层面，系统研究TDP-43对tau致病相关因素的作用，探讨TDP-43和tau病理的关系，揭示TDP-43在AD与CTE患者脑tau病理发生发展中的作用和分子机制，为该类疾病的防治提供分子生物学依据。

异常过度磷酸化的tau聚集形成的神经元纤维缠结是阿尔茨海默病(AD)和慢性创伤性脑损伤(CTE)的共同病理特征，而2/3的AD和85%的CTE伴有TDP-43病理聚集，但是tau与TDP-43的关系不明。本项目从分子、细胞和整体等多层面，研究了TDP-43对tau mRNA稳定性、tau外显子10可变剪接的调节及机制，探讨了TDP-43异常在tau病理改变中的作用，分析了AD患者脑中TDP-43异常与tau病理改变的关系，系统研究TDP-43对tau致病相关因素的作用，探讨TDP-43和tau病理的关系。我们发现：1）TDP-43通过与tau mRNA的3'-UTR结合，增加tau mRNA的不稳定性，促进tau mRNA的降解，抑制tau的表达；2）TDP-43促进tau外显子10的编码，有利于4R-tau的表达；3）TDP-43的截断和磷酸化促进其细胞质转位并聚集，抑制其调节tau mRNA加工的功能；4）小鼠局灶性脑损伤可引起急性、慢性AD样改变，但没有明显的tau磷酸化增加和TDP-43异常；5）在TDP-43M337V的转基因小鼠脑中，总tau的表达及3R-tau/4R-tau比例增加；6）在AD患者脑中TDP-43的表达降低，并与总tau的表达和3R-tau/4R-tau比例增加相关；7）CK1ε有效地磷酸化TDP-43，促进TDP-43在细胞质聚集，抑制其在tau mRNA加工中的作用。在AD患者脑中，CK1ε表达明显增加，TDP-43磷酸化水平增加，并与总tau和3R-tau的表达增加相关，CK1ε的表达增加与TDP-43和tau的病理相关。因此，本研究揭示了TDP-43在AD与CTE患者脑tau病理发生发展中的作用和分子机制，为该类疾病的防治提供分子生物学依据。