A γ-Secretase Inhibitor, but Not a γ-Secretase Modulator, Induced Defects in BDNF Axonal Trafficking and Signaling: Evidence for a Role for APP
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{"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", "type"=>"journal", "authors"=>[{"first_name"=>"April M.", "last_name"=>"Weissmiller", "scopus_author_id"=>"55428020400"}, {"first_name"=>"Orlangie", "last_name"=>"Natera-Naranjo", "scopus_author_id"=>"25951486000"}, {"first_name"=>"Sol M.", "last_name"=>"Reyna", "scopus_author_id"=>"54910195600"}, {"first_name"=>"Matthew L.", "last_name"=>"Pearn", "scopus_author_id"=>"36705041300"}, {"first_name"=>"Xiaobei", "last_name"=>"Zhao", "scopus_author_id"=>"57191265251"}, {"first_name"=>"Phuong", "last_name"=>"Nguyen", "scopus_author_id"=>"36554725100"}, {"first_name"=>"Soan", "last_name"=>"Cheng", "scopus_author_id"=>"56030452200"}, {"first_name"=>"Lawrence S.B.", "last_name"=>"Goldstein", "scopus_author_id"=>"7402499550"}, {"first_name"=>"Rudolph E.", "last_name"=>"Tanzi", "scopus_author_id"=>"56916740300"}, {"first_name"=>"Steven L.", "last_name"=>"Wagner", "scopus_author_id"=>"7402232858"}, {"first_name"=>"William C.", "last_name"=>"Mobley", "scopus_author_id"=>"7006497542"}, {"first_name"=>"Chengbiao", "last_name"=>"Wu", "scopus_author_id"=>"7501665750"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84923590684", "pmid"=>"25710492", "sgr"=>"84923590684", "doi"=>"10.1371/journal.pone.0118379", "issn"=>"19326203", "pui"=>"602498409"}, "id"=>"6b6f266a-47cd-39b6-9366-9ed3450df64e", "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.", "link"=>"http://www.mendeley.com/research/%CE%B3secretase-inhibitor-not-%CE%B3secretase-modulator-induced-defects-bdnf-axonal-trafficking-signaling-evid", "reader_count"=>31, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>6, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Librarian"=>1, "Researcher"=>6, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>8, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>4, "Neuroscience"=>7, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Neuroscience"=>{"Neuroscience"=>7}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1922769"], "description"=>"<p><b>A</b>: A diagram depicts APP processing and the pathways that GSI or GSM treatment differentially affects Aβ peptide formation and the production of APP C-terminal fragments (APP CTFs). First, β-secretase or α-secretase cleaves APP, leading to the production of either β-CTF or α-CTF. Cleavage of β-CTF by γ-secretase at multiple sites yields several Aβ peptides and the APP intracellular domain (AICD). Cleavage of α-CTF by γ-secretase gives rise to and AICD and the P3 fragment. <b>B</b>: Differential effects of GSI and GSM on the production of Aβ species and APP β-CTF [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118379#pone.0118379.ref034\" target=\"_blank\">34</a>–<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118379#pone.0118379.ref036\" target=\"_blank\">36</a>]. Rat E18 cortical neurons (DIV7) were treated with GSI BMS-299897 (<b>C</b>) or sGSM41 (<b>D</b>) for 24 hrs. The media were harvested and levels of Aβ species (Aβ38, 40, 42) in the media were measured as described in Materials and Methods (n = 3, *P < 0.05, **P < 0.01 using student’s <i>t</i>-test). Treatment with 1μM BMS-299897 or 2.5μM sGSM41 showed the most robust effect and these conditions were used in all other experiments herein. <b>E</b>: Western blotting analyses showing the processing of two substrates of γ-secretase, APP and N-cadherin, in cortical neurons treated with vehicle (0.1% DMSO), 1μM BMS-299897, 2.5μM sGSM41 for 24 hrs. <b>F</b>: Quantitative measurement of mRNA levels by real-time PCR in cortical neurons treated as in <b>E</b>. The mRNA levels are normalized to mRNA levels of β-actin (n = 3, mean±S.E., p values represent results of Student’s <i>t</i>-test).</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316909, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g001", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_effects_of_BMS_299897_and_sGSM41_on_APP_processing_/1316909", "title"=>"Differential effects of BMS-299897 and sGSM41 on APP processing.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922782", "https://ndownloader.figshare.com/files/1922783", "https://ndownloader.figshare.com/files/1922784", "https://ndownloader.figshare.com/files/1922785", "https://ndownloader.figshare.com/files/1922786", "https://ndownloader.figshare.com/files/1922787"], "description"=>"<div><p>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.</p></div>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316922, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0118379.s001", "https://dx.doi.org/10.1371/journal.pone.0118379.s002", "https://dx.doi.org/10.1371/journal.pone.0118379.s003", "https://dx.doi.org/10.1371/journal.pone.0118379.s004", "https://dx.doi.org/10.1371/journal.pone.0118379.s005", "https://dx.doi.org/10.1371/journal.pone.0118379.s006"], "stats"=>{"downloads"=>0, "page_views"=>44, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_947_Secretase_Inhibitor_but_Not_a_947_Secretase_Modulator_Induced_Defects_in_BDNF_Axonal_Trafficking_and_Signaling_Evidence_for_a_Role_for_APP_/1316922", "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", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922777"], "description"=>"<p>Samples were prepared as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118379#pone.0118379.g004\" target=\"_blank\">Fig. <b>4A</b></a>. The ultra-structures of hippocampal neurites were examined using transmission electron microscopy as described in Materials and Methods. For each treatment condition, representative images of 9300x, 18500x and Zoom-in are shown. Asterisk denotes a single mitochondrion, arrows point to vesicles. EM data were verified by two independent researchers at the Cellular and Molecular Medicine Electron Microscopy Facility at UCSD.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316917, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g005", "stats"=>{"downloads"=>0, "page_views"=>44, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BMS_299897_not_sGSM41_induces_clustering_of_mitochondria_within_processes_of_rat_E18_hippocampal_neurons_/1316917", "title"=>"BMS-299897, not sGSM41, induces clustering of mitochondria within processes of rat E18 hippocampal neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922773"], "description"=>"<p><b>A</b>: Experimental design for examining distribution of mitochondria and synaptic vesicle precursors within neuronal processes. Rat E18 hippocampal neurons at DIV4 were treated every 24 hrs with vehicle, BMS-299897 or sGSM41. Neurons at DIV7 were either labeled with MitoTracker for analysis of mitochondria (<b>B-D</b>) or fixed and stained for synaptophysin with a specific antibody (<b>E-G</b>). <b>B</b>: Representative images of DIC and MitoTracker under each treatment conditions. The density of mitochondria (<b>C</b>) and the measurement of mitochondrial profile (<b>D</b>) are quantitated and presented (n = 15–20 neurites for vehicle, sGSM41 samples. For BMS-299897-treated samples, n = 95–150 puncta, mean±S.E., ***P<0.001). <b>E</b>: Representative images of DIC and synaptophysin immmunostaining for each treatment condition. The density of mitochondria (<b>F</b>) and the measurement of mitochondrial profile (<b>G</b>) are quantitated and presented (For density analysis, n = 29–40 neurites, mean±S.E., *P<0.05. For profile measurement, n = 26–27 puncta). Scale bar = 20μm.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316913, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g004", "stats"=>{"downloads"=>1, "page_views"=>57, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BMS_299897_not_sGSM41_alters_the_distribution_of_mitochondria_and_synaptophysin_positive_vesicles_within_processes_of_rat_E18_hippocampal_neurons_/1316913", "title"=>"BMS-299897, not sGSM41, alters the distribution of mitochondria and synaptophysin-positive vesicles within processes of rat E18 hippocampal neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922771"], "description"=>"<p><b>A</b>: Microfluidic chamber cultures of rat E18 hippocampal neurons for live imaging of axonal transport of QD-BDNF. At DIV7, neurons were treated with vehicle, BMS-299-897 or sGSM41 followed by live imaging as described in Materials and Methods. DA: distal axon; CB: cell body; DR: dendrites; PA: proximal axon. <b>B</b>: Representative kymographs generated from a 90 sec time lapse series (captured at 1frame/s) of axonal movement of QD-BDNF are shown. <b>C</b>: Distribution of instantaneous velocities of individual QD-BDNF molecules moving in the retrograde direction under each treatment condition with the mean values marked as red horizontal lines. Time-lapse recordings were collected from at least three independent experiments for each treatment conditions with 15–20 separate movies being collected blindly from each sample. The data represent 70–125 QD-BDNF molecules. <b>D</b>: Analysis of the average distance travelled by QD-BDNF molecules for each treatment condition. <b>E</b>: Breakdown of transport directionalities (Retro: retrograde, Antero: anterograde, and Stationary) of all QD-BDNF signals under each treatment condition. The percentiles for each direction are shown. The data in <b>D</b>, <b>E</b> represent mean±S.E from three independent experiments. All p values were calculated using student’s <i>t</i>-test.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316911, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g002", "stats"=>{"downloads"=>0, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BMS_299897_not_sGSM41_induces_deficits_in_retrograde_axonal_trafficking_of_QD_BDNF_/1316911", "title"=>"BMS-299897, not sGSM41, induces deficits in retrograde axonal trafficking of QD-BDNF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922772"], "description"=>"<p>Rat E18 cortical neurons were either cultured in 12-well plate (mass cultures) (<b>A-D</b>) or in microfluidic biochemistry chambers (<b>E-H</b>) to treat and harvest axons only. Neurons were pretreated with vehicle, BMS-299897, sGSM41 for 24 hrs followed by stimulation with 50ng/ml BDNF as indicated. Equal amounts of protein lysates were analyzed by SDS/PAGE and immunoblotting with specific antibodies as indicated (<b>A</b>). Semi-quantitative results are shown for the level of activated TrkB (pTrkB in <b>B</b>), activated Akt1 (pAkt1 in <b>C</b>) and activated Erk1/2 (pErk1/2 in <b>D</b>) (mean±S.E., n = 3 for pTrkB, n = 5 for pAkt1, n = 5 for pERK1/2, *P = 0.04, ***P<0.001 using Student’s <i>t</i>-test). <b>E</b>: Diagram of microfluidic biochemistry chambers used for axonal signaling assays. <b>F</b>: Western blotting analyses of lysates from the distal axon chamber (DA) and cell body chamber (CB). Samples from CB samples are enriched for the dendritic protein, MAP2 and samples from DA are enriched for Tau. Total samples from the distal chambers were compared against 1/4<sup>th</sup> of lysates from the cell body chamber collected from the same experiment. Both CB and DA chambers were pretreated with vehicle, sGSM41 or BMS-299897 and only distal axonal chambers were treated with BDNF (50ng/ml) for 0, 5 min. <b>G</b>: Axonal lysates were analyzed by SDS-PAGE/immunoblotting for the level of pErk1/2, total Erk1/2 and β-actin. The results in G that are normalized against β-actin (mean±S.E., n = 3, *P<0.05) are shown in <b>H</b>. All signaling data analyzed are from 3 or more separate experiments.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316912, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g003", "stats"=>{"downloads"=>1, "page_views"=>29, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_effects_of_BMS_299897_and_sGSM41_on_BDNF_TrkB_mediated_signaling_pathways_/1316912", "title"=>"Differential effects of BMS-299897 and sGSM41 on BDNF/TrkB-mediated signaling pathways.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922781"], "description"=>"<p><b>A</b>: Western blotting analysis of typical siRNA-mediated knockdown effect on full length APP and APP CTFs. Rat E18 hippocampal neurons (DIV5) were transfected with siRNA against APP or control siRNA for 72 hrs followed by drug treatment for 24 hrs. On average, the protein levels of APP and APP CTF were knocked down to 70% of normal levels. <b>B</b>: Live imaging of axonal transport of QD-BDNF was performed as in <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0118379#pone.0118379.g002\" target=\"_blank\">Fig. 2</a></b>and representative kymographs of QD-BDNF movement (60 sec) within axons are shown for each condition. Retrograde direction is indicated. Analysis of QD-BDNF for average velocities (<b>C</b>) and directionality of QD-BDNF movement (<b>D</b>) revealed that knocking down APP prior to BMS-299897 treatment partially rescued the deficits in both the velocities and directionality of QD-BDNF as seen previously. 15–20 separate movies were collected and analyzed for each chamber. The data represent 50–130 QD-BDNF molecules (mean±S.E.). Neurons that were cultured in microfluidic chambers were transfected with siRNA and treated with BMS-299897 as in <b>A</b>. BDNF (50 ng/ml, final concentration) was added to the distal axon chambers only for 30 min. Neurons were fixed and stained for pCREB using a specific antibody. The nuclei were stained with the Hoechst dye. Representative images are shown in <b>E</b> and quantitative analysis of the percentage of nuclei that were pCREB-positive is shown in <b>F</b> (mean±S.E., n = 10 images, **P = 0.004). All images were obtained on a Leica DMI6000B inverted microscope (scale bar = 50μm).</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316921, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g007", "stats"=>{"downloads"=>0, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Knockdown_of_APP_rescues_deficits_in_velocity_and_directionality_of_axonally_transported_QD_BDNF_induced_by_BMS_299897_/1316921", "title"=>"Knockdown of APP rescues deficits in velocity and directionality of axonally transported QD-BDNF induced by BMS-299897.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/1922780"], "description"=>"<p><b>A</b>: Experimental paradigm for examining the effect of sustained treatment with vehicle, BMS-299897 or sGSM41 on neuronal morphology of rat E18 hippocampal neurons. 3-day treatment and 8-day treatment were chosen to assess early and late changes in neuronal morphology. <b>B</b>: Representative images of MAP2 staining for each conditions at Day 3 or 8. <b>C</b>: Quantitative analysis of soma size (n = 25–30 neurons, mean±S.E., ***P<0.001). <b>D</b>: Quantitative analysis of number of primary dendrites (n = 17–25 neurons, mean±S.E, ***P<0.001). <b>E</b>: Sholl analysis of neuronal tracings for 8 day treatment with vehicle, BMS-299897 or sGSM41.</p>", "links"=>[], "tags"=>["amyloid precursor protein", "BDNF trafficking", "GSM", "APP Clues", "neuropathological features", "Induced Defects", "APP processing", "GSI effects", "Alzheimer disease", "BDNF axonal trafficking", "ad", "novel class", "APP CTFs", "Synaptic vesicles", "axonal trafficking"], "article_id"=>1316920, "categories"=>["Biological Sciences"], "users"=>["April M. Weissmiller", "Orlangie Natera-Naranjo", "Sol M. Reyna", "Matthew L. Pearn", "Xiaobei Zhao", "Phuong Nguyen", "Soan Cheng", "Lawrence S. B. Goldstein", "Rudolph E. Tanzi", "Steven L. Wagner", "William C. Mobley", "Chengbiao Wu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0118379.g006", "stats"=>{"downloads"=>0, "page_views"=>34, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sustained_treatment_with_BMS_299897_but_not_GSM_causes_marked_changes_in_soma_size_and_dendritic_complexity_in_rat_E18_hippocampal_neurons_/1316920", "title"=>"Sustained treatment with BMS-299897, but not GSM, causes marked changes in soma size and dendritic complexity in rat E18 hippocampal neurons.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-02-24 03:08:36"}

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  • {"unique-ip"=>"13", "full-text"=>"13", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"5", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"14", "full-text"=>"16", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"15", "full-text"=>"12", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"7", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"22", "full-text"=>"15", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"17", "full-text"=>"15", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"13", "full-text"=>"15", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"5", "full-text"=>"8", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"8", "full-text"=>"8", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"10", "full-text"=>"11", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"16", "full-text"=>"14", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2019", "month"=>"9"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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