Multifunctional roles of APL-1 in C. elegans
Item
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Title
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Multifunctional roles of APL-1 in C. elegans
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Identifier
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d_2009_2013:5af05286ad5d:10786
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identifier
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11060
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Creator
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Ewald, Collin Y.,
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Contributor
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Christine Li
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Date
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2011
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Language
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English
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Publisher
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City University of New York.
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Subject
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Neurosciences | aging | Alzheimer's Disease | apl-1 | daf-16 | development | learning
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Abstract
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Alzheimer's disease is an age-dependent disorder and the most common type of dementia. The most prevalent mutations associated with familial Alzheimer's Disease are found in the gene encoding the amyloid precursor protein (APP) or in the presenilin genes, which encode proteases that cleave APP. In mice, knockout of the APP gene family leads to lethality and type II lissencephaly, while overexpression of APP causes a shortening in lifespan and learning defects. However, the cellular function of APP and the pathways in which APP acts are unknown.;Here we investigate the role of APL-1, the Caenorhabditis elegans orthologue of APP. Specifically, we expressed APL-1 with different promoters to determine the effect of APL-1 overexpression on several parameters: lifespan, development, and learning. Overexpression of APL-1 driven by its endogenous promoter accelerated aging and thereby shortened lifespan. By contrast, overexpression of APL-1 driven by the snb-1 promoter slowed aging and thereby prolonged lifespan. This extended lifespan was dependent on signals from the gonad and activity of the transcription factor DAF-16/FOXO and the nuclear hormone receptor DAF-12/NHR. Several other APL-1 overexpression phenotypes, including slowed developmental progression, were also dependent on daf-16/FOXO and daf-12/NHR activity. Lastly, pan-neuronal expression of APL-1 caused impairments in olfactory and gustatory avoidance behaviors as well as impairments in touch habituation. These defects were rescued by decreased activity of daf-16/FOXO and daf-12/NHR. Our results suggest that signaling of neuronally expressed APL-1 perturbs learning via the insulin/IGF-1 and the TGF-beta pathways. Hence, APL-1 is a multifunctional protein that signals in multiple pathways to affect lifespan, development, and learning. In light of our results, we suggest that the shortened lifespan and learning defects in mice with APP overexpression might be mediated via the insulin/IGF-1 pathway. Interestingly, AD is strongly associated with type 2 diabetes and some AD patients show brain specific diabetes.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biology
