RESUMO
Two common conjugated linoleic acids (LAs), cis-9, trans-11 CLA (c9,t11 CLA) and trans-10, cis-12 CLA (t10,c12 CLA), exert various biological activities. However, the effect of CLA on the generation of neurotoxic amyloid-ß (Aß) protein remains unclear. We found that c9,t11 CLA significantly suppressed the generation of Aß in mouse neurons. CLA treatment did not affect the level of ß-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment, or Aß protein precursor (APP) in cultured neurons. BACE1 and γ-secretase activities were not directly affected by c9,t11 CLA. Localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, the predominant site of APP cleavage by BACE1. The level of CLA-containing phosphatidylcholine (CLA-PC) increased dramatically in neurons incubated with CLA. Incorporation of phospholipids containing c9,t11 CLA, but not t10,c12 CLA, into the membrane may affect the localization of some membrane-associated proteins in intracellular membrane compartments. Thus, in neurons treated with c9,t11 CLA, reduced colocalization of APP with BACE1 in late endosomes may decrease APP cleavage by BACE1 and subsequent Aß generation. Our findings suggest that the accumulation of c9,t11 CLA-PC/LPC in neuronal membranes suppresses the production of neurotoxic Aß in neurons.
Assuntos
Peptídeos beta-Amiloides/biossíntese , Ácido Linoleico/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Neurônios/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Células Cultivadas , Suplementos Nutricionais , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Fosfatidilcolinas/metabolismoRESUMO
ATBP [(A+T)-stretch binding protein] activates the Sarcophaga defense protein genes in an (A+T)-stretch dependent manner as shown previously using a luciferase reporter assay [Aozasa et al. (2001) Eur J Biochem, 268, 2506-2511]. We identified the Drosophila homologue of ATBP. Drosophila ATBP has 388 amino acid residues and the amino acid sequence has high similarity with that of the Sarcophaga ATBP. In particular, residues 1-56 and 301-374 are highly conserved between Sarcophaga and Drosophila. Drosophila ATBP activated the Sarcophaga lectin gene promoter in SL-2 cells. The Drosophila ATBP gene is a single copy gene and is located in the 20E region of chromosome X.