ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 71 citations in OpenAlex.
- Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.European journal of clinical pharmacology · 2013Pooled it
- Aβ1-15/16 as a potential diagnostic marker in neurodegenerative diseases.Neuromolecular medicine · 2013Trial
- Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2012Trial
- Chemical strategies for brain delivery of genomic therapy.Nature reviews. Chemistry · 2025Review
- Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system.Nature biotechnology · 2025Article
- Blood-brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system.Nature materials · 2025Article
- Lipid Nanoparticles Enhance mRNA Delivery to the Central Nervous System Upon Intrathecal Injection.Advanced materials (Deerfield Beach, Fla.) · 2025Article
- Enantioconvergent copper-catalysed difluoromethylation of alkyl halides.Nature catalysis · 2024Article
- The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.Molecular neurodegeneration · 2023Article
- Flavonoids and fibrate modulate apoE4-induced processing of amyloid precursor protein in neuroblastoma cells.Frontiers in neuroscience · 2023Article
- Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.Communications biology · 2022Article
- Comparative neuropathology in aging primates: A perspective.American journal of primatology · 2021Review
- Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance.The oncologist · 2021Review
- Deubiquitylation and stabilization of Notch1 intracellular domain by ubiquitin-specific protease 8 enhance tumorigenesis in breast cancer.Cell death and differentiation · 2020Article
- Bridging the Gap Between Fluid Biomarkers for Alzheimer's Disease, Model Systems, and Patients.Frontiers in aging neuroscience · 2020Review
- SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases.Nature reviews. Neurology · 2019Review
- Article
- Inhibition of γ-Secretase Leads to an Increase in Presenilin-1.Molecular neurobiology · 2018Article
- A Translational Systems Pharmacology Model for Aβ Kinetics in Mouse, Monkey, and Human.CPT: pharmacometrics & systems pharmacology · 2017Article
- BMS-708163 and Nilotinib restore synaptic dysfunction in human embryonic stem cell-derived Alzheimer's disease models.Scientific reports · 2016Article
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable-isotope-labeling, and dose-dependently reduced newly generated CNS Abeta. In contrast to systemic Abeta metabolism, CNS Abeta production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Abeta, including C-terminal truncated forms of Abeta: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.