Academic journal article Genetics

APL-1, the Alzheimer's Amyloid Precursor Protein in Caenorhabditis Elegans, Modulates Multiple Metabolic Pathways throughout Development

Academic journal article Genetics

APL-1, the Alzheimer's Amyloid Precursor Protein in Caenorhabditis Elegans, Modulates Multiple Metabolic Pathways throughout Development

Article excerpt

ABSTRACT Mutations in the amyloid precursor protein (APP) gene or in genes that process APP are correlated with familial Alzheimer's disease (AD). The biological function of APP remains unclear. APP is a transmembrane protein that can be sequentially cleaved by different secretases to yield multiple fragments, which can potentially act as signaling molecules. Caenorhabditis elegans encodes one APP-related protein, APL-1, which is essential for viability. Here, we show that APL-1 signaling is dependent on the activity of the FOXO transcription factor DAF-16 and the nuclear hormone receptor DAF-12 and influences metabolic pathways such as developmental progression, body size, and egg-laying rate. Furthermore, apl-1(yn5) mutants, which produce high levels of the extracellular APL-1 fragment, show an incompletely penetrant temperature-sensitive embryonic lethality. In a genetic screen to isolate mutants in which the apl-1(yn5) lethality rate is modified, we identified a suppressor mutation in MOA-1/R155.2, a receptor-protein tyrosine phosphatase, and an enhancer mutation in MOA-2/B0495.6, a protein involved in receptor-mediated endocytosis. Knockdown of apl-1 in an apl-1(yn5) background caused lethality and molting defects at all larval stages, suggesting that apl-1 is required for each transitional molt. We suggest that signaling of the released APL-1 fragment modulates multiple metabolic states and that APL-1 is required throughout development.

THE cause of Alzheimer's disease (AD) remains unknown. Mutations in several genes, including the amyloid precursor protein (APP), are correlated with inherited forms of AD. Furthermore, a defining feature of AD is large numbers of senile plaques in the brain, and the plaques' major component is a cleavage byproduct of APP. The normal function of APP and its cleavage products is still unclear. Here, we report that the Caenorhabditis elegans APP-related protein APL-1 has multiple functions during development, including modulating the insulin pathway. These results indicate that human APP may similarly regulate metabolic processes, such as the insulin pathway.

AD is a neurodegenerative disorder that leads to cognitive decline (Alzheimer's Association 2010). One postmortem criterion in the diagnosis of AD is the presence of senile plaques in AD patients (Kidd 1964; Luse and Smith 1964; Terry et al. 1964; Krigman et al. 1965). The major component of the senile plaques is the b-amyloid peptide, which is a cleavage fragment of APP (Kang et al. 1987). Mutations and duplications of APP have been correlated with familial Alzheimer's disease (Chartier-Harlin et al. 1991; Goate et al. 1991; Murrell et al. 1991; Cabrejo et al. 2006; Rovelet- Lecrux et al. 2006; Sleegers et al. 2006). APP is a single pass transmembrane domain protein (Kang et al. 1987), which can be cleaved by either an a- or a b-secretase to release a large extracellular fragment (sAPPa or sAPPb, respectively); the remaining transmembrane fragment is subsequently cleaved by the g-secretase to release a small intracellular fragment (APP intracellular domain, AICD) and, in the case of a previous b-secretase cleavage, the b-amyloid peptide (reviewed in Gralle and Ferreira 2007). The biological functions of the cleaved APP fragments, sAPPa/b and AICD, remain unclear. Crystal structures of sAPP revealed a growth-factor-like domain that is conserved and present in all mammalian APP-family members as well in C. elegans and Drosophila orthologs (Rossjohn et al. 1999), consistent with a growth factor role reported in vitro (reviewed in Mattson 1997; Schmitz et al. 2002). Conversely, fragments of sAPPb can act as a ligand that directly binds death receptor 6 (DR6) to initiate neurodegeneration (Nikolaev et al. 2009; Kuester et al. 2011). In vivo sAPP can act as a co-factor to promote cell proliferation of ventricular zone cells (Caille et al. 2004). However, determining the function of APP in mammals is complicated by two functionally redundant proteins, APLP1 and APLP2. …

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