ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer's Disease.Alzheimer's research & therapy · 2024Trial
- Chronic pain in Alzheimer disease and the role of neuroimmune interactions.Pharmacological reviews · 2026Review
- Photobiomodulation in experimental models of Alzheimer's disease: state-of-the-art and translational perspectives.Alzheimer's research & therapy · 2024Review
- A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease.medRxiv : the preprint server for health sciences · 2024Article
- The Alzheimer's disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130.Molecular neurodegeneration · 2023Article
- Article
- The metabolism of human soluble amyloid precursor protein isoforms is quantifiable by a stable isotope labeling-tandem mass spectrometry method.Scientific reports · 2022Article
- Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways.Communications biology · 2022Article
- Using stable isotope labeling to advance our understanding of Alzheimer's disease etiology and pathology.Journal of neurochemistry · 2021Review
- Pimavanserin, a 5HTJournal of neurochemistry · 2021Article
- Shenqi Xingnao Granules ameliorates cognitive impairments and Alzheimer's disease-like pathologies in APP/PS1 mouse model.Chinese herbal medicines · 2020Article
- SILK studies - capturing the turnover of proteins linked to neurodegenerative diseases.Nature reviews. Neurology · 2019Review
- Central pharmacodynamic activity of solanezumab in mild Alzheimer's disease dementia.Alzheimer's & dementia (New York, N. Y.) · 2018Article
- Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future.Journal of Alzheimer's disease : JAD · 2018Review
- Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage.Journal of Alzheimer's disease : JAD · 2017Article
- A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis.The Journal of biological chemistry · 2016Review
- Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ-54861911, a potent oral BACE inhibitor.Alzheimer's & dementia (New York, N. Y.) · 2016Article
- AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics.Journal of Alzheimer's disease : JAD · 2016Article
- Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms.Frontiers in neuroscience · 2016Review
- Article
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Authors and funding
21 authors at 2 institutions in 2 countries.
Funding
Abstract
BACE, a β-secretase, is an attractive potential disease-modifying therapeutic strategy for Alzheimer's disease (AD) as it results directly in the decrease of amyloid precursor protein (APP) processing through the β-secretase pathway and a lowering of CNS amyloid-β (Aβ) levels. The interaction of the β-secretase and α-secretase pathway-mediated processing of APP in the rhesus monkey (nonhuman primate; NHP) CNS is not understood. We hypothesized that CNS inhibition of BACE would result in decreased newly generated Aβ and soluble APPβ (sAPPβ), with increased newly generated sAPPα. A stable isotope labeling kinetics experiment in NHPs was performed with a (13)C6-leucine infusion protocol to evaluate effects of BACE inhibition on CNS APP processing by measuring the kinetics of sAPPα, sAPPβ, and Aβ in CSF. Each NHP received a low, medium, or high dose of MBI-5 (BACE inhibitor) or vehicle in a four-way crossover design. CSF sAPPα, sAPPβ, and Aβ were measured by ELISA and newly incorporated label following immunoprecipitation and liquid chromatography-mass spectrometry. Concentrations, kinetics, and amount of newly generated APP fragments were calculated. sAPPβ and sAPPα kinetics were similar, but both significantly slower than Aβ. BACE inhibition resulted in decreased labeled sAPPβ and Aβ in CSF, without observable changes in labeled CSF sAPPα. ELISA concentrations of sAPPβ and Aβ both decreased and sAPPα increased. sAPPα increased by ELISA, with no difference by labeled sAPPα kinetics indicating increases in product may be due to APP shunting from the β-secretase to the α-secretase pathway. These results provide a quantitative understanding of pharmacodynamic effects of BACE inhibition on NHP CNS, which can inform about target development.
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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.