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

Leal M.C., Magnani N., Villordo S., Buslje C.M., Evelson P., Castano E.M., Morelli L.

Studies of post-mortem brains from Alzheimer disease patients suggest that oxidative damage induced by mitochondrial amyloid β (mitAβ) accumulation is associated with mitochondrial dysfunction. However, the regulation of mitAβ metabolism is unknown. One of the proteases involved in mitAβ 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-1α/NRF-1). A strong positive correlation between PGC-1α 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 mitAβ and impaired mitochondrial respiration. These changes were restored by inhibition of γ-secretase or promotion of mitochondrial biogenesis. Our results suggest that IDE-Met(1) links the mitochondrial biogenesis pathway with mitAβ levels and organelle functionality.

J. Biol. Chem. 288:12920-12931(2013) [PubMed] [Europe PMC]

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