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TGF-ß induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid ß plaques in Alzheimer's disease.
Lee, M-H; Lin, S-R; Chang, J-Y; Schultz, L; Heath, J; Hsu, L-J; Kuo, Y-M; Hong, Q; Chiang, M-F; Gong, C-X; Sze, C-I; Chang, N-S.
Afiliação
  • Lee MH; Institute of Molecular Medicine, National Cheng Kung University College of Medicine, Taiwan, ROC.
Cell Death Dis ; 1: e110, 2010 Dec 23.
Article em En | MEDLINE | ID: mdl-21368882
The role of a small transforming growth factor beta (TGF-ß)-induced TIAF1 (TGF-ß1-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-ß1 and environmental stress (e.g., alterations in pericellular environment) may induce TIAF1 self-aggregation in a type II TGF-ß 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 ß (Aß) aggregates are 17 and 48%, respectively, in the nondemented and AD groups, suggesting that TIAF1 aggregation occurs preceding formation of Aß. To test this hypothesis, in vitro analysis showed that TGF-ß-regulated TIAF1 aggregation leads to dephosphorylation of amyloid precursor protein (APP) at Thr668, followed by degradation and generation of APP intracellular domain (AICD), Aß and amyloid fibrils. Polymerized TIAF1 physically interacts with amyloid fibrils, which would favorably support plaque formation in vivo.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Peptídeos beta-Amiloides / Fator de Crescimento Transformador beta / Placa Amiloide / Proteínas Reguladoras de Apoptose / Doença de Alzheimer Tipo de estudo: Etiology_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2010 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Peptídeos beta-Amiloides / Fator de Crescimento Transformador beta / Placa Amiloide / Proteínas Reguladoras de Apoptose / Doença de Alzheimer Tipo de estudo: Etiology_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2010 Tipo de documento: Article