Abstract
The role of a small transforming growth factor beta (TGF-β)-induced TIAF1 (TGF-β1-induced antiapoptotic factor) in the pathogenesis of Alzheimer's disease (AD) was investigated. TIAF1 physically interacts with mothers against DPP homolog 4 (Smad4), and blocks SMAD-dependent promoter activation when overexpressed. Accordingly, knockdown of TIAF1 by small interfering RNA resulted in spontaneous accumulation of Smad proteins in the nucleus and activation of the promoter governed by the SMAD complex. TGF-β1 and environmental stress (e.g., alterations in pericellular environment) may induce TIAF1 self-aggregation in a type II TGF-β receptor-independent manner in cells, and Smad4 interrupts the aggregation. Aggregated TIAF1 induces apoptosis in a caspase-dependent manner. 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 amyloid precursor protein (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.
Highlights
Role of transforming growth factor beta (TGF-b) in the pathogenesis of Alzheimer’s disease (AD) is controversial.[2,3,4,5] Type II receptor for TGF-b (TbRII) is central to the TGF-b/mothers against DPP homolog (Smad) signaling
Stimulation of COS7 fibroblasts with TGF-b1 for 30 min resulted in the binding of endogenous TGF-b1-induced antiapoptotic factor (TIAF1) with Smad[4], and the complex was accumulated in the nuclei (Figure 1b)
COS7 cells were transfected with enhanced green fluorescence protein (EGFP)-Smad[4] plasmid and simultaneously infected with retroviral TIAF1si or empty retrovirus
Summary
Role of transforming growth factor beta (TGF-b) in the pathogenesis of AD is controversial.[2,3,4,5] Type II receptor for TGF-b (TbRII) is central to the TGF-b/mothers against DPP homolog (Smad) signaling. Reduced levels of TbRII are observed in human AD brains, and this correlates with age-dependent neurodegeneration and AD-like disease in a mouse model.[2] in a transgenic AD mouse model, TGF-b1 is constitutively upregulated and neuronal apoptosis occurs.[3] Increased levels of TGF-b in AD are associated with perivascular deposition of extracellular matrix, which hinders clearance of Ab and allows the development of cerebral amyloid angiopathy.[4] Blockade of TGF-b/Smad innate immune signaling mitigates Alzheimer-like pathology in transgenic TbRII mouse model.[5]. We identified TGF-b1-induced antiapoptotic factor (TIAF1) protein aggregation, which may cause neuronal death. TIAF1 self-aggregation leads to generation of Ab and amyloid fibrils from amyloid precursor protein (APP) in vitro
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