Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid ? (A?) peptide catabolism and functionality.

ABSTRACT: Studies of post-mortem brains from Alzheimer disease patients suggest that oxidative damage induced by mitochondrial amyloid ? (mitA?) accumulation is associated with mitochondrial dysfunction. However, the regulation of mitA? metabolism is unknown. One of the proteases involved in mitA? catabolism is the long insulin-degrading enzyme (IDE) isoform (IDE-Met(1)). However, the mechanisms of its expression are unknown, and its presence in brain is uncertain. We detected IDE-Met(1) in brain and showed that its expression is regulated by the mitochondrial biogenesis pathway (PGC-1?/NRF-1). A strong positive correlation between PGC-1? or NRF-1 and long IDE isoform transcripts was found in non-demented brains. This correlation was weaker in Alzheimer disease. In vitro inhibition of IDE increased mitA? and impaired mitochondrial respiration. These changes were restored by inhibition of ?-secretase or promotion of mitochondrial biogenesis. Our results suggest that IDE-Met(1) links the mitochondrial biogenesis pathway with mitA? levels and organelle functionality.

SUBMITTER: Leal MC 

PROVIDER: S-EPMC3642335 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature