TDP-43 interaction with the intracellular domain of amyloid precursor protein induces p53-associated apoptosis

TAR DNA-binding protein 43 (TDP-43), an essential pathological protein in both amyotrophic later sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), is expressed abnormally in Alzheimer's disease (AD). However, whether and how TDP-43 contributes the pathogenesis of AD remains unknown. We have shown here a colocalization between TDP-43 and the intracellular domain of APP (AICD) in the nucleus. Coimmunoprecipitation analysis showed an interaction between TDP-43 and AICD. Overexpression of TDP-43 in COS7 cells enhanced the transactivation of AICD in an APP-Gal4 luciferase reporter system. Real-time PCR analysis showed that cotransfection of TDP-43 and AICD in HEK293 cells increased P53 mRNA levels compared to either TDP-43-transfected or AICD-transfected cells. Moreover, cotransfection of TDP-43 and AICD in either N2a or COS7 cells showed increased numbers of apoptotic cells compared to either TDP-43-transfected or AICD-transfected cells, indicating that TDP-43 enhances AICD-mediated apoptosis in N2a or COS7 cells. Thus, TDP-43 may play a role in AD pathology through interaction with AICD.