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.
Keywords:
Amyloid; Mitochondrial Metabolism; Neurodegeneration; Protease; Transcription Factors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism*
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Brain / metabolism*
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Brain / pathology
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HEK293 Cells
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HeLa Cells
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Insulysin / genetics
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Insulysin / metabolism*
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondria / pathology
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Respiratory Factor 1 / genetics
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Nuclear Respiratory Factor 1 / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Rats
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Rats, Sprague-Dawley
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Amyloid beta-Peptides
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Heat-Shock Proteins
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Mitochondrial Proteins
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NRF1 protein, human
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Nerve Tissue Proteins
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Nuclear Respiratory Factor 1
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PPARGC1A protein, human
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, rat
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RNA-Binding Proteins
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Transcription Factors
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Amyloid Precursor Protein Secretases
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Insulysin