title: A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP.
abstract: Clues to Alzheimer disease (AD) pathogenesis come from a variety of different sources including studies of clinical and neuropathological features, biomarkers, genomics and animal and cellular models. An important role for amyloid precursor protein (APP) and its processing has emerged and considerable interest has been directed at the hypothesis that Aβ peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Aβ peptides have been discovered such as γ-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Aβ levels through very different mechanisms. However, GSIs, but not GSMs, markedly increase the levels of APP CTFs that are increasingly viewed as disrupting neuronal function. Here, we evaluated the effects of GSIs and GSMs on a number of neuronal phenotypes possibly relevant to their use in treatment of AD. We report that GSI disrupted retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF), suppressed BDNF-induced downstream signaling pathways and induced changes in the distribution within neuronal processes of mitochondria and synaptic vesicles. In contrast, treatment with a novel class of GSMs had no significant effect on these measures. Since knockdown of APP by specific siRNA prevented GSI-induced changes in BDNF axonal trafficking and signaling, we concluded that GSI effects on APP processing were responsible, at least in part, for BDNF trafficking and signaling deficits. Our findings argue that with respect to anti-amyloid treatments, even an APP-specific GSI may have deleterious effects and GSMs may serve as a better alternative.
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: April M
authors.initials: AM
authors.lastname: Weissmiller
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Orlangie
authors.initials: O
authors.lastname: Natera-Naranjo
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Sol M
authors.initials: SM
authors.lastname: Reyna
authors.affiliation: Department of Anesthesiology, University of California San Diego, San Diego, California, United States of America; V.A. San Diego Healthcare System, San Diego, California, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Pearn
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Soan
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California, United States of America.
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.affiliation: Department of Neurosciences, University of California San Diego, San Diego, California, United States of America.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Wu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001369:Axons / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000737:chemistry / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D018613:Microscopy, Confocal; D018715:Microscopy, Video; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D045663:Quantum Dots / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013572:Synaptic Vesicles / Q000378:metabolism
chemical_list: C497115:4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D002087:Butyrates; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases