Abstract
Beta-amyloid peptides that are cleaved from the amyloid precursor protein (APP) play a critical role in Alzheimer's disease (AD) pathophysiology. Here, we show that in Drosophila, the targeted expression of the key genes of AD, APP, the beta-site APP-cleaving enzyme BACE, and the presenilins led to the generation of beta-amyloid plaques and age-dependent neurodegeneration as well as to semilethality, a shortened life span, and defects in wing vein development. Genetic manipulations or pharmacological treatments with secretase inhibitors influenced the activity of the APP-processing proteases and modulated the severity of the phenotypes. This invertebrate model of amyloid plaque pathology demonstrates Abeta-induced neurodegeneration as a basic biological principle and may allow additional genetic analyses of the underlying molecular pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology*
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Amyloid Precursor Protein Secretases
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Animals, Genetically Modified
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Aspartic Acid Endopeptidases / genetics
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Aspartic Acid Endopeptidases / metabolism
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Disease Models, Animal*
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Disease Progression
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila*
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Endopeptidases / metabolism
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Gene Targeting
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Heredodegenerative Disorders, Nervous System / metabolism
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Heredodegenerative Disorders, Nervous System / pathology*
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mutation
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Phenotype
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Photoreceptor Cells, Invertebrate / pathology
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Plaque, Amyloid / metabolism
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Plaque, Amyloid / pathology*
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Presenilins
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Protein Processing, Post-Translational / physiology
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Retina / metabolism
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Retina / pathology
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Survival Rate
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Transgenes
Substances
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Amyloid beta-Protein Precursor
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Drosophila Proteins
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Membrane Proteins
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Presenilins
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Psn protein, Drosophila
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Amyloid Precursor Protein Secretases
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Endopeptidases
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Aspartic Acid Endopeptidases
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BACE1 protein, human