ArticlePloS one2015
A γ-secretase inhibitor, but not a γ-secretase modulator, induced defects in BDNF axonal trafficking and signaling: evidence for a role for APP.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 37 citations in OpenAlex.
- Molecular interplay between Non-coding RNAs and BDNF in Neurodegenerative Disorders: a systematic review.Molecular biology reports · 2026Pooled it
- Article
- Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function.International journal of molecular sciences · 2024Article
- Alzheimer's disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling.bioRxiv : the preprint server for biology · 2024Article
- γ-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of γ-Secretase.Seminars in cell & developmental biology · 2020Review
- Pharmacokinetic and Pharmacodynamic Effects of a γ-Secretase Modulator, PF-06648671, on CSF Amyloid-β Peptides in Randomized Phase I Studies.Clinical pharmacology and therapeutics · 2020Article
- Review
- Herpes Simplex Virus, Alzheimer's Disease and a Possible Role for Rab GTPases.Frontiers in cell and developmental biology · 2019Article
- Decoupling the Effects of the Amyloid Precursor Protein From Amyloid-β Plaques on Axonal Transport Dynamics in the Living Brain.Frontiers in cellular neuroscience · 2019Article
- T-complex protein 1-ring complex enhances retrograde axonal transport by modulating tau phosphorylation.Traffic (Copenhagen, Denmark) · 2018Article
- Swedish Nerve Growth Factor Mutation (NGFThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Dysregulation of Rab5-mediated endocytic pathways in Alzheimer's disease.Traffic (Copenhagen, Denmark) · 2018Review
- Dysregulation of neurotrophin signaling in the pathogenesis of Alzheimer disease and of Alzheimer disease in Down syndrome.Free radical biology & medicine · 2018Review
- PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease.Brain : a journal of neurology · 2017Article
- Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson's disease.Scientific reports · 2017Article
- Enhanced neuroinvasion by smaller, soluble prions.Acta neuropathologica communications · 2017Article
- Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer's Disease Mutations.Cell reports · 2016Article
- TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington's disease.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration.The Journal of clinical investigation · 2016Article
- Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF.Neurobiology of aging · 2016Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
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.
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