title: Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration.
abstract: The processing of Amyloid Precursor Proteins (APPs) results in several fragments, including soluble N-terminal ectodomains (sAPPs) and C-terminal intracellular domains (AICD). sAPPs have been ascribed neurotrophic or neuroprotective functions in cell culture, although β-cleaved sAPPs can have deleterious effects and trigger neuronal cell death. Here we describe a neuroproprotective function of APP and fly APPL (Amyloid Precursor Protein-like) in vivo in several Drosophila mutants with progressive neurodegeneration. We show that expression of the N-terminal ectodomain is sufficient to suppress the progressive degeneration in these mutants and that the secretion of the ectodomain is required for this function. In addition, a protective effect is achieved by expressing kuzbanian (which has α-secretase activity) whereas expression of fly and human BACE aggravates the phenotypes, suggesting that the protective function is specifically mediated by the α-cleaved ectodomain. Furthermore, genetic and molecular studies suggest that the N-terminal fragments interact with full-length APPL activating a downstream signaling pathway via the AICD. Because we show protective effects in mutants that affect different genes (AMP-activated protein kinase, MAP1b, rasGAP), we propose that the protective effect is not due to a genetic interaction between APPL and these genes but a more general aspect of APP proteins. The result that APP proteins and specifically their soluble α-cleaved ectodomains can protect against progressive neurodegeneration in vivo provides support for the hypothesis that a disruption of the physiological function of APP could play a role in the pathogenesis of Alzheimer's Disease.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, Oregon Health & Sciences University, Portland, OR 97239, USA.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Wentzell
authors.forename: Bonnie J
authors.initials: BJ
authors.lastname: Bolkan
authors.forename: Katia
authors.initials: K
authors.lastname: Carmine-Simmen
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Swanson
authors.forename: Derek T
authors.initials: DT
authors.lastname: Musashe
authors.forename: Doris
authors.initials: D
authors.lastname: Kretzschmar
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D018450:Disease Progression; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; C066839:Appl protein, Drosophila; D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins