TDP43 is a newly identified substrate for PS1, enhancing the expression of APP following cleavage.

Alzheimer's disease (AD) has been comprehensively studied; however, most research has focused on Aβ plaque deposition and Tau protein phosphorylation. Emerging evidence suggests that TDP43 may be significantly involved AD and potentially worsening its pathology. To investigate the role of TDP43 in the pathological development of AD, we employed the STRING protein network interaction tool to identify potential relationships between TDP43 and other proteins, including PS1 and APP. Subsequent co-immunoprecipitation experiments were conducted, and the results indicated that TDP43 could interact with PS1. Further studies have shown that the interaction between the two would also lead to the loss of nuclear localization of TDP43. We also found that overexpression or knockdown of PS1 in both primary cells, HeLa and NSC34 cells indicated that TDP43 is likely to be a substrate of PS1. Subsequent use of the L685,458 and z-VAD, the PS1 mutant plasmids D257A and D385A, and bioinformatics approaches demonstrated that PS1 is dependent on γ-secretase and caspase activity to cleave TDP43, and that the cleavage site is at amino acid 315 of TDP43. Besides, our study demonstrated that the interaction of TDP43 with PS1 in primary cells, HeLa and NSC34 cells can promote APP expression, resulting in elevated Aβ levels. Finally, we investigated whether the interaction between TDP43 and PS1 affects the expression of other PS1 substrates, Notch and E-cadherin. Our results demonstrated that TDP43 cleaved by PS1 only promoted APP expression and had no effect on other PS1 substrates. In conclusion, these results suggest that TDP43 is a new substrate of PS1 and that TDP43 cleaved by PS1 promotes APP expression, which leads to increased Aβ content, which may explain why TDP43 promotes AD development. These insights enhance our understanding of TDP43's role in AD development.