Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila.
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.
Greeve
Isabell
I
Center for Molecular Neurobiology, University of Hamburg, 20251 Hamburg, Germany.
Kretzschmar
Doris
D
Tschäpe
Jakob-Andreas
JA
Beyn
Anika
A
Brellinger
Claire
C
Schweizer
Michaela
M
Nitsch
Roger M
RM
Reifegerste
Rita
R
D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D018390:Gene Targeting; D020271:Heredodegenerative Disorders, Nervous System / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D053763:Presenilins; D011499:Protein Processing, Post-Translational / Q000502:physiology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D019076:Transgenes
D016564:Amyloid beta-Protein Precursor; D029721:Drosophila Proteins; D008565:Membrane Proteins; D053763:Presenilins; C106427:Psn protein, Drosophila; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human