Abstract
Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full-length human APP in Drosophila and established a fly AD model that exhibits multiple AD-like symptoms. Here we report that depletion of CHIP effectively palliated APP-induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for APP-induced autophagy dysfunction, which promotes Aβ production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal APP activity, but also contributes to dysregulated APP metabolism and subsequent AD pathogenesis.
Keywords:
CHIP; APP; Alzheimer’s disease; Aβ; autophagy.
© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Amyloid beta-Protein Precursor / toxicity
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Animals
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Aspartic Acid Endopeptidases / metabolism
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Autophagy / genetics*
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Brain / metabolism
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Cognitive Dysfunction / genetics
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Disease Models, Animal
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Dopaminergic Neurons / metabolism
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Down-Regulation
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Drosophila / metabolism*
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Eye / growth & development
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Eye / metabolism
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Learning Disabilities / genetics
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Locomotion / genetics
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Longevity / genetics
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Presenilins / metabolism
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RNA Interference
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Wings, Animal / metabolism
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Wings, Animal / pathology
Substances
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Amyloid beta-Protein Precursor
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Chi protein, Drosophila
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Drosophila Proteins
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Nuclear Proteins
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Presenilins
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Psn protein, Drosophila
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Aspartic Acid Endopeptidases
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Bace protein, Drosophila