Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration

Jill S. Wentzell, Bonnie J. Bolkan, Katia Carmine-Simmen, Tracy L. Swanson, Derek T. Musashe, Doris Kretzschmar

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)78-87
Number of pages10
JournalNeurobiology of Disease
Volume46
Issue number1
DOIs
Publication statusPublished - Apr 2012

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Keywords

  • APP
  • APPL
  • Drosophila
  • Neurodegeneration
  • Neuroprotection

ASJC Scopus subject areas

  • Neurology

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