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Journal article
Cyclopamine Modulates gamma-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation
The Journal of biological chemistry, v 289(48), pp 33258-33274
28 Nov 2014
PMID: 25281744
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Alzheimer disease (AD) is a progressive neurodegenerative disease leading to memory loss. Numerous lines of evidence suggest that amyloid-beta (A beta), a neurotoxic peptide, initiates a cascade that results in synaptic dysfunction, neuronal death, and eventually cognitive deficits. A beta is generated by the proteolytic processing of the amyloid precursor protein (APP), and alterations to this processing can result in Alzheimer disease. Using in vitro and in vivo models, we identified cyclopamine as a novel regulator of gamma-secretase-mediated cleavage of APP. We demonstrate that cyclopamine decreases A beta generation by altering APP retrograde trafficking. Specifically, cyclopamine treatment reduced APP-C-terminal fragment (CTF) delivery to the trans-Golgi network where gamma-secretase cleavage occurs. Instead, cyclopamine redirects APP-CTFs to the lysosome. These data demonstrate that cyclopamine treatment decreases gamma-secretase-mediated cleavage of APP. In addition, cyclopamine treatment decreases the rate of APP-CTF degradation. Together, our data demonstrate that cyclopamine alters APP processing and A beta generation by inducing changes in APP subcellular trafficking and APP-CTF degradation.
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Details
- Title
- Cyclopamine Modulates gamma-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation
- Creators
- Anna G. Vorobyeva - Drexel UniversityRandall Lee - Drexel UniversitySean Miller - Drexel UniversityCharles Longen - the Departments of Pharmacology and Physiology.Michal Sharoni - Drexel UniversityPreeti J. Kandelwal - Drexel UniversityFelix J. Kim - the Departments of Pharmacology and Physiology.Daniel R. Marenda - Drexel UniversityAleister J. Saunders - Drexel University
- Publication Details
- The Journal of biological chemistry, v 289(48), pp 33258-33274
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 17
- Grant note
- R01NS057295 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01NS057295 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Drexel University
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000345636600018
- Scopus ID
- 2-s2.0-84912536036
- Other Identifier
- 991019201387504721
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- Web of Science research areas
- Biochemistry & Molecular Biology