TIAF1 self‐aggregation precedes amyloid beta formation in vivo

The role of a small TGF‐β‐induced TIAF1 in the pathogenesis of Alzheimer's disease (AD) was investigated. TGF‐β1 and environmental stress (e.g. alterations in pericellular environment) induces TIAF1 self‐aggregation, and Smad4 of the TGF‐β pathway interrupts the aggregation. By filter retardation assay, TIAF1 aggregates were found in the hippocampi of nondemented humans and AD patients. Total TIAF1‐positive samples containing amyloid β (Aβ) aggregates are 17% and 48%, respectively, in the nondemented and AD groups, suggesting that TIAF1 aggregation occurs preceding formation of Aβ. To test this hypothesis, in vitro analysis showed that TGF‐β‐regulated TIAF1 aggregation leads to dephosphorylation of APP at Thr668, followed by degradation and generation of APP intracellular domain (AICD), Aβ and amyloid fibrils. Polymerized TIAF1 physically interacts with amyloid fibrils, which would favorably support plaque formation in vivo. (Supported by National Science Council and National Health Research Institute, Taiwan, and Department of Defense, USA)