Transcriptional regulation of Insulin Degrading Enzyme modulates mitochondrial Aβ catabolism and functionality

LEAL MARÍA CELESTE; MAGNANI NATALIA; VILLORDO SERGIO; MARINO BUSLJE CRISTINA; EVELSON PABLO; CASTAÑO EDUARDO; MORELLI LAURA

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2013 vol. 288 p. 12920 - 12931

0021-9258

Studies of postmortem brains from Alzheimer?s disease (AD) patients suggest that oxidative damage induced by mitochondrial Aβ (mitAβ) accumulation is associated with mitochondrial dysfunction. However, the regulation of mitAβ metabolism is unknown. One of the proteases involved in mitAβ catabolism is long Insulin-Degrading Enzyme (IDE) isoform (IDE-Met1). Yet, the mechanisms of its expression are unknown and its presence in brain uncertain. We detected IDE-Met1 in brain and showed that its expression is regulated by mitochondrial biogenesis pathway (PGC-1α/NRF-1). A strong positive correlation between PGC-1α or NRF-1 and L-IDE transcripts was found in nondemented brains. This correlation was weaker in AD. In vitro inhibition of IDE increased mitAβ and impaired mitochondrial respiration. These changes were restored by inhibition of - secretase or promotion of mitochondrial biogenesis. Our results suggest that IDE-Met1 links mitochondrial biogenesis pathway with mitAβ levels and organella functionality