Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid β (Aβ) peptide catabolism and functionality

LEAL MC; MAGNANI N; VILLORDO S; MARINO BUSJLE C; EVELSON P; CASTAÑO EM; MO

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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

0021-9258

Studies of post-mortem brains from Alzheimer diseasepatients suggest that oxidative damage induced by mitochondrialamyloid (mitA) accumulation is associated with mitochondrialdysfunction. However, the regulation of mitAmetabolism is unknown. One of the proteases involved in mitAcatabolism is the long insulin-degrading enzyme (IDE) isoform(IDE-Met1). However, the mechanisms of its expression areunknown, and its presence in brain is uncertain. We detectedIDE-Met1 in brain and showed that its expression is regulated bythe mitochondrial biogenesis pathway (PGC-1/NRF-1). Astrong positive correlation between PGC-1 or NRF-1 and longIDE isoform transcripts was found in non-demented brains.This correlation was weaker in Alzheimer disease. In vitro inhibitionof IDE increased mitA and impaired mitochondrial respiration.These changes were restored by inhibition of -secretaseor promotion of mitochondrial biogenesis. Our resultssuggest that IDE-Met1 links the mitochondrial biogenesis pathwaywith mitA levels and organelle functionality.