TIAF1 self‐aggregation is essential for Aβ plaque formation in the human hippocampus

Abstract

Role of TIAF1 in the TGF‐β pathway leading to the pathogenesis of Alzheimer's disease (AD) was investigated. We determined that TIAF1 bound Smad4 and blocked its‐regulated promoter activation. TGF‐β1 induced self‐aggregation of transiently overexpressed TIAF1 in a type II TGF‐β receptor (TβRII)‐independent manner. The resulting TIAF1 aggregates upregulated amyloid precursor protein (APP) and superinduced Aβ aggregate formation, which leads to apoptosis essentially in every cell. Smad4 and dominant negative TIAF1 blocked the formation of TIAF1 aggregation. TIAF1 aggregates were found in degenerating and dead neurons, and the interface between metastatic cancer cells and brain cells. By filter retardation assay, TIAF1 aggregates were shown in the hippocampi of postmortem nondemented humans (age 59.3±16.3, n=24), which possessed low levels of Aβ aggregates and Smad4 barely detectable. Co‐presence of TIAF1 with Aβ is 17.7%, but is significantly increased up to 80% in AD patients (age 81.8±9.3, n=60). To reproduce the in vivo observations, neuroblastoma cells were cultured on cancer cell matrices, or co‐cultured with cancer cells, and shown to have induced TIAF1/Aβ aggregates. Together, occurrence of TIAF1 self‐aggregation in the human hippocampus is essential for Aβ plaque formation, indicating a novel mechanism of AD pathogenesis. [supported by NSC and NHRI, Taiwan and DoD, USA]