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J Biol Chem. 2013 May 3;288(18):12920-31. doi: 10.1074/jbc.M112.424820. Epub 2013 Mar 22.

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

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  • 1Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires (Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)), Avenida Patricias Argentinas 435, Ciudad Autónoma de Buenos Aires C1405BWE, Argentina.


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.


Amyloid; Mitochondrial Metabolism; Neurodegeneration; Protease; Transcription Factors

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