Amyloid precursor proteins are protective in Drosophila models of progressive neurodegeneration

NEUROBIOLOGY OF DISEASE

卷:46

Article

Wentzell, Jill S.¹  Bolkan, Bonnie J.¹  Carmine-Simmen, Katia¹  Swanson, Tracy L.²  Musashe, Derek T.¹  Kretzschmar, Doris¹ 

[1] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97239 USA

[2] Oregon Hlth & Sci Univ, Dept Cell & Dev Biol, Portland, OR 97239 USA

关键词: APP;    APPL;    Neuroprotection;    Neurodegeneration;    Drosophila;   

DOI  :  10.1016/j.nbd.2011.12.047

来源: Elsevier

【 摘 要 】

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 beta-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 a-secretase activity) whereas expression of fly and human BACE aggravates the phenotypes, suggesting that the protective function is specifically mediated by the a-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 alpha-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. (C) 2012 Elsevier Inc. All rights reserved.

【 授权许可】

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