title: Cyclopamine modulates γ-secretase-mediated cleavage of amyloid precursor protein by altering its subcellular trafficking and lysosomal degradation.
abstract: Alzheimer disease (AD) is a progressive neurodegenerative disease leading to memory loss. Numerous lines of evidence suggest that amyloid-β (Aβ), a neurotoxic peptide, initiates a cascade that results in synaptic dysfunction, neuronal death, and eventually cognitive deficits. Aβ 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 γ-secretase-mediated cleavage of APP. We demonstrate that cyclopamine decreases Aβ generation by altering APP retrograde trafficking. Specifically, cyclopamine treatment reduced APP-C-terminal fragment (CTF) delivery to the trans-Golgi network where γ-secretase cleavage occurs. Instead, cyclopamine redirects APP-CTFs to the lysosome. These data demonstrate that cyclopamine treatment decreases γ-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 Aβ generation by inducing changes in APP subcellular trafficking and APP-CTF degradation.
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and.
authors.forename: Anna G
authors.initials: AG
authors.lastname: Vorobyeva
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and.
authors.forename: Randall
authors.initials: R
authors.lastname: Lee
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and.
authors.forename: Sean
authors.initials: S
authors.lastname: Miller
authors.affiliation: the Departments of Pharmacology and Physiology.
authors.forename: Charles
authors.initials: C
authors.lastname: Longen
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and.
authors.forename: Michal
authors.initials: M
authors.lastname: Sharoni
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and.
authors.forename: Preeti J
authors.initials: PJ
authors.lastname: Kandelwal
authors.affiliation: the Departments of Pharmacology and Physiology.
authors.forename: Felix J
authors.initials: FJ
authors.lastname: Kim
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and Neurobiology and Anatomy, and.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Marenda
authors.affiliation: From the Department of Biology, Drexel University, Philadelphia, Pennsylvania 19104 and Neurobiology and Anatomy, and Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102 Aleister.Saunders@drexel.edu.
authors.forename: Aleister J
authors.initials: AJ
authors.lastname: Saunders
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004331:Drosophila melanogaster; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D014704:Veratrum Alkaloids / Q000494:pharmacology*; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D014704:Veratrum Alkaloids; D053829:Amyloid Precursor Protein Secretases; C000541:cyclopamine
keywords: Alzheimer Disease; Amyloid Precursor Protein (APP); Amyloid-β (Aβ); Intracellular Trafficking; Lysosome; Sterol; γ-Secretase