Please use this identifier to cite or link to this item: https://doi.org/10.1186/s13195-015-0137-y
DC FieldValue
dc.titleModulation of Aβ42 in vivo by γ-secretase modulator in primates and humans
dc.contributor.authorLing, I.-F
dc.contributor.authorGolde, T.E
dc.contributor.authorGalasko, D.R
dc.contributor.authorKoo, E.H
dc.date.accessioned2020-10-27T05:38:33Z
dc.date.available2020-10-27T05:38:33Z
dc.date.issued2015
dc.identifier.citationLing, I.-F, Golde, T.E, Galasko, D.R, Koo, E.H (2015). Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans. Alzheimer's Research and Therapy 7 (1) : 55. ScholarBank@NUS Repository. https://doi.org/10.1186/s13195-015-0137-y
dc.identifier.issn17589193
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/180902
dc.description.abstractIntroduction: Ibuprofen is one of the nonsteroidal anti-inflammatory drugs that have been shown to selectively lower pathogenic amyloid beta-peptide (Aβ)42 without impairing overall γ-secretase activity in vitro. This γ-secretase modulator (GSM) activity has been hypothesized to contribute to the reduction in risk of developing Alzheimer's disease in chronic users of nonsteroidal anti-inflammatory drugs. However, it is unclear whether ibuprofen, within therapeutic dosing range, demonstrates GSM activity in humans. In this study, we evaluated the effects of ibuprofen and a second-generation GSM, GSM-1, on Aβ levels in cerebrospinal fluid and plasma of young nonhuman primates and humans. Methods: Five to seven conscious cynomolgus monkeys (Macaca fascicularis) were nontreated or treated with 30 mg/kg GSM-1 or 50 or 100 mg/kg ibuprofen and the plasma and cerebrospinal fluid were sampled at -8, 0 (baseline or right before treatment), 2, 4, 6, 8, 12, and 24 h postdosing. In addition, sixteen healthy human subjects were randomly assigned to receive either placebo or 800 mg ibuprofen given by intravenous administration and plasma were collected at 0 (before drug infusion), 0.5, 1, 2, 4, 6, 8, 10, and 24 h after dosing. Results: A single dose of GSM-1 (30 mg/kg) decreased the ratio of Aβ42 to Aβ40 to 60 % in plasma and the ratio of Aβ42 to total Aβ to 65 % in cerebrospinal fluid from baseline to postdosing in monkeys. However, no significant changes were detected following ibuprofen treatment at 100 mg/kg. Consistent with the results from nonhuman primates, ibuprofen did not alter plasma Aβ levels in human volunteers after a single 800 mg dose. Conclusions: GSM-1 exerted potent lowering of the ratio of Aβ42 to Aβ40 in nonhuman primates but the hypothesized GSM activity of ibuprofen could not be demonstrated in nonhuman primates and humans after acute dosing. © 2015 Ling et al.
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceUnpaywall 20201031
dc.subjectamyloid beta protein
dc.subjectamyloid precursor protein
dc.subjectgamma secretase
dc.subjectgamma secretase inhibitor
dc.subjectibuprofen
dc.subjectindometacin
dc.subjectnonsteroid antiinflammatory agent
dc.subjectplacebo
dc.subjectsulindac sulfide
dc.subjectamyloid beta protein
dc.subjectamyloid beta protein[1-40]
dc.subjectamyloid beta-protein (1-42)
dc.subjectamyloid precursor protein
dc.subjectAPP protein, human
dc.subjectibuprofen
dc.subjectnonsteroid antiinflammatory agent
dc.subjectpeptide fragment
dc.subjectsecretase
dc.subjectAlzheimer disease
dc.subjectanimal experiment
dc.subjectArticle
dc.subjectcerebrospinal fluid
dc.subjectCHO cell line
dc.subjectcontrolled study
dc.subjectdegenerative disease
dc.subjectdrug blood level
dc.subjectelectrospray
dc.subjectfemale
dc.subjectgene mutation
dc.subjecthuman
dc.subjectin vitro study
dc.subjectin vivo study
dc.subjectMacaca fascicularis
dc.subjectneuromodulation
dc.subjectnonhuman
dc.subjectnuclear magnetic resonance
dc.subjectprimate
dc.subjectpriority journal
dc.subjectprotein cleavage
dc.subjectrisk reduction
dc.subjectsingle drug dose
dc.subjectthin layer chromatography
dc.subjectadult
dc.subjectanimal
dc.subjectblood
dc.subjectCricetulus
dc.subjectdose response
dc.subjectgenetics
dc.subjectmale
dc.subjectmetabolism
dc.subjectrandomization
dc.subjecttime factor
dc.subjecttreatment outcome
dc.subjectyoung adult
dc.subjectAdult
dc.subjectAmyloid beta-Peptides
dc.subjectAmyloid beta-Protein Precursor
dc.subjectAmyloid Precursor Protein Secretases
dc.subjectAnimals
dc.subjectAnti-Inflammatory Agents, Non-Steroidal
dc.subjectCHO Cells
dc.subjectCricetulus
dc.subjectDose-Response Relationship, Drug
dc.subjectFemale
dc.subjectHumans
dc.subjectIbuprofen
dc.subjectMacaca fascicularis
dc.subjectMale
dc.subjectPeptide Fragments
dc.subjectRandom Allocation
dc.subjectTime Factors
dc.subjectTreatment Outcome
dc.subjectYoung Adult
dc.typeArticle
dc.contributor.departmentMEDICINE
dc.description.doi10.1186/s13195-015-0137-y
dc.description.sourcetitleAlzheimer's Research and Therapy
dc.description.volume7
dc.description.issue1
dc.description.page55
dc.published.statePublished
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