Transcriptional regulation of insulin-degrading enzyme (IDE): Possible role of hypoxia and Notch.

SURACE EI; LEAL MC; BULLOJ A; CASTAñO EM; MORELLI L

Mar del Plata, Argentina

Congreso; SAIB 43th Annual Meeting.; 2007

Sociedad Argentina de Bioquimica y Biología Molecular

Amyloid beta (Aâ) is accumulated in the brains of Alzheimer’s disease (AD) patients and its steady-state level is regulated by the expression and activity of IDE. Here, we determined the effect of presenilin-1 (PS1; the catalytic subunit of g-secretase involved in Aâ generation) and hypoxia (a known risk factor for sporadic AD) in the modulation of IDE expression. First, rat primary astrocytic cultures or CHO cells were placed in hypoxia (0.1% O2) and IDE mRNA levels measured by RT-PCR. We observed a significant increase in IDE mRNA levels in both cell types in hypoxia compared to normoxia (23%). Interestingly, CHO cells stably expressing PS1 exhibited decreased IDE mRNA levels in hypoxia while a PS1 dominant-negative mutant partially rescues this phenotype. This suggests the existence of a g-secretase-dependent transcriptional inhibitory mechanism. HEY proteins are known Notch- and HIF-1-á- mediated transcriptional repressors. Transfection of HEY into wild-type CHO cells significantly reduced IDE transcription (50%). Co-transfection of Notch intracellular domain and HIF-1-á completely abrogated IDE mRNA levels. Overall, we show that IDE expression is modulated in hypoxia in a gamma-secretase manner. Also, we describe, for the first time, an IDE transcriptional inhibitory mechanism mediated by HEY which may be relevant in the pathogenesis of sporadic AD.