PMID- 25710492 OWN - NLM STAT- MEDLINE DCOM- 20151117 LR - 20230829 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 10 IP - 2 DP - 2015 TI - A gamma-secretase inhibitor, but not a gamma-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP. PG - e0118379 LID - 10.1371/journal.pone.0118379 [doi] LID - e0118379 AB - 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 Abeta peptides induce changes central to pathogenesis. Accordingly, molecules that reduce the levels of Abeta peptides have been discovered such as gamma-secretase inhibitors (GSIs) and modulators (GSMs). GSIs and GSMs reduce Abeta 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. FAU - Weissmiller, April M AU - Weissmiller AM AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Natera-Naranjo, Orlangie AU - Natera-Naranjo O AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Reyna, Sol M AU - Reyna SM AD - Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California, United States of America. FAU - Pearn, Matthew L AU - Pearn ML AD - 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. FAU - Zhao, Xiaobei AU - Zhao X AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Nguyen, Phuong AU - Nguyen P AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Cheng, Soan AU - Cheng S AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Goldstein, Lawrence S B AU - Goldstein LS AD - Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California, United States of America. FAU - Tanzi, Rudolph E AU - Tanzi RE AD - Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America. FAU - Wagner, Steven L AU - Wagner SL AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Mobley, William C AU - Mobley WC AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. FAU - Wu, Chengbiao AU - Wu C AD - Department of Neurosciences, University of California San Diego, San Diego, California, United States of America. LA - eng GR - RF1 AG048083/AG/NIA NIH HHS/United States GR - P01 AG015379/AG/NIA NIH HHS/United States GR - P50 AG005131/AG/NIA NIH HHS/United States GR - R01 AG032180/AG/NIA NIH HHS/United States GR - R01 MH060009/MH/NIMH NIH HHS/United States GR - P50 AG005134/AG/NIA NIH HHS/United States GR - R13 AG026970/AG/NIA NIH HHS/United States GR - R37 MH060009/MH/NIMH NIH HHS/United States GR - R01 NS045860/NS/NINDS NIH HHS/United States GR - K08 GM124500/GM/NIGMS NIH HHS/United States GR - RF1 AG048080/AG/NIA NIH HHS/United States GR - P30 AG062421/AG/NIA NIH HHS/United States GR - P30 NS047101/NS/NINDS NIH HHS/United States GR - R01 AG014713/AG/NIA NIH HHS/United States GR - AG032180/AG/NIA NIH HHS/United States GR - P01 AG004953/AG/NIA NIH HHS/United States GR - PN2 EY016525/EY/NEI NIH HHS/United States GR - T32 GM008666/GM/NIGMS NIH HHS/United States GR - L40 GM125142/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150224 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (4-(2-((1R)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Butyrates) RN - 0 (Enzyme Inhibitors) RN - 0 (Hydrocarbons, Halogenated) RN - 0 (RNA, Small Interfering) RN - EC 3.4.- (Amyloid Precursor Protein Secretases) SB - IM MH - Alzheimer Disease/metabolism/pathology MH - Amyloid Precursor Protein Secretases/*antagonists & inhibitors/chemistry/metabolism MH - Amyloid beta-Protein Precursor/antagonists & inhibitors/genetics/*metabolism MH - Axons/*metabolism MH - Brain-Derived Neurotrophic Factor/chemistry/*metabolism MH - Butyrates/pharmacology MH - Cells, Cultured MH - Enzyme Inhibitors/pharmacology MH - Humans MH - Hydrocarbons, Halogenated/pharmacology MH - Microscopy, Confocal MH - Microscopy, Video MH - Mitochondria/metabolism MH - Neurons/cytology/drug effects/metabolism MH - Protein Transport/drug effects MH - Quantum Dots/chemistry MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Signal Transduction/drug effects MH - Synaptic Vesicles/metabolism PMC - PMC4339551 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2015/02/25 06:00 MHDA- 2015/11/18 06:00 PMCR- 2015/02/24 CRDT- 2015/02/25 06:00 PHST- 2014/11/11 00:00 [received] PHST- 2015/01/14 00:00 [accepted] PHST- 2015/02/25 06:00 [entrez] PHST- 2015/02/25 06:00 [pubmed] PHST- 2015/11/18 06:00 [medline] PHST- 2015/02/24 00:00 [pmc-release] AID - PONE-D-14-50248 [pii] AID - 10.1371/journal.pone.0118379 [doi] PST - epublish SO - PLoS One. 2015 Feb 24;10(2):e0118379. doi: 10.1371/journal.pone.0118379. eCollection 2015.