title: Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid β (Aβ) peptide catabolism and functionality.
abstract: 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.
authors.affiliation: Fundación 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.
authors.forename: María C
authors.initials: MC
authors.lastname: Leal
authors.forename: Natalia
authors.initials: N
authors.lastname: Magnani
authors.forename: Sergio
authors.initials: S
authors.lastname: Villordo
authors.forename: Cristina Marino
authors.initials: CM
authors.lastname: Buslje
authors.forename: Pablo
authors.initials: P
authors.lastname: Evelson
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Castaño
authors.forename: Laura
authors.initials: L
authors.lastname: Morelli
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006360:Heat-Shock Proteins; D024101:Mitochondrial Proteins; C495633:NRF1 protein, human; D009419:Nerve Tissue Proteins; D051266:Nuclear Respiratory Factor 1; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D007339:Insulysin
keywords: Amyloid; Mitochondrial Metabolism; Neurodegeneration; Protease; Transcription Factors