A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:26948580", "kind": "science-record", "revision": 6, "content_hash": "sha256:56aeb38a187a9dc5e1306a26ee0fba1c897ca61e114e57e942902d7f8bb76d4d", "created_at": "2026-11-01T15:40:16Z", "updated_at": "2026-11-01T21:20:26Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.", "doi": "10.1186/s13195-016-0178-x", "pmid": "26948580", "authors": ["Mikko Hölttä", "Robert A Dean", "Eric Siemers", "Kwasi G Mawuenyega", "Wendy Sigurdson", "Patrick C May", "David M Holtzman", "Erik Portelius", "Henrik Zetterberg", "Randall J Bateman", "Kaj Blennow", "Johan Gobom"], "journal": "Alzheimer's research & therapy", "year": 2016, "abstract": "BACKGROUND: In Alzheimer's disease, beta-amyloid peptides in the brain aggregate into toxic oligomers and plaques, a process which is associated with neuronal degeneration, memory loss, and cognitive decline. One therapeutic strategy is to decrease the production of potentially toxic beta-amyloid species by the use of inhibitors or modulators of the enzymes that produce beta-amyloid from amyloid precursor protein (APP). The failures of several such drug candidates by lack of effect or undesired side-effects underscore the importance to monitor the drug effects in the brain on a molecular level. Here we evaluate if peptidomic analysis in cerebrospinal fluid (CSF) can be used for this purpose.\nMETHODS: Fifteen human healthy volunteers, divided into three groups, received a single dose of placebo or either 140 mg or 280 mg of the γ-secretase inhibitor semagacestat (LY450139). Endogenous peptides in CSF, sampled prior to administration of the drug and at six subsequent time points, were analyzed by liquid chromatography coupled to mass spectrometry, using isobaric labeling based on the tandem mass tag approach for relative quantification.\nRESULTS: Out of 302 reproducibly detected peptides, 11 were affected by the treatment. Among these, one was derived from APP and one from amyloid precursor-like protein 1. Nine peptides were derived from proteins that may not be γ-secretase substrates per se, but that are regulated in a γ-secretase-dependent manner.\nCONCLUSIONS: These results indicate that a CSF peptidomic approach may be a valuable tool both to verify target engagement and to identify other pharmacodynamic effects of the drug. Data are available via ProteomeXchange with identifier PXD003075.\nTRIAL REGISTRATION: NCT00765115 , registered 30/09/2008.", "claims": [{"id": "claim-method", "statement": "Because peptide abundances cannot be assumed to be normally distributed, the non-parametric Friedman test in the software PASW Statistics 18 (IBM) was used to evaluate the remaining peptides, employing a significance threshold of p < 0.05.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26948580", "locator": "sections[5] \"Data analysis\" paragraph 5", "quote": "Because peptide abundances cannot be assumed to be normally distributed, the non-parametric Friedman test in the software PASW Statistics 18 (IBM) was used to evaluate the remaining peptides, employing a significance threshold of p < 0.05."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium [20] via the PRIDE partner repository with the dataset identifier PXD003075 and 10.6019/PXD003075\".", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26948580", "locator": "sections[5] \"Data analysis\" paragraph 2", "quote": "The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium [20] via the PRIDE partner repository with the dataset identifier PXD003075 and 10.6019/PXD003075\"."}], "state": "complete"}, {"id": "claim-target-result", "statement": "A non-parametric Friedman test (p < 0.05) showed that 11 of 302 reproducibly detected CSF peptides were affected by semagacestat treatment; the source data are available through ProteomeXchange under identifier PXD003075.", "kind": "quantitative", "target": {"value": 0.05, "unit": "p-value", "tolerance": null, "source": "Of these, 11 peptides were significantly affected (p < 0.05) by treatment with semagacestat (Table 2)."}, "evidence": [{"asset": "source:pmid:26948580", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Out of 302 reproducibly detected peptides, 11 were affected by the treatment."}, {"asset": "source:pmid:26948580", "locator": "sections[6] \"Results\" paragraph 2", "quote": "Of these, 11 peptides were significantly affected (p < 0.05) by treatment with semagacestat (Table 2)."}, {"asset": "source:pmid:26948580", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "Data are available via ProteomeXchange with identifier PXD003075."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "A non-parametric Friedman test (p < 0.05) showed that 11 of 302 reproducibly detected CSF peptides were affected by semagacestat treatment; the source data are available through ProteomeXchange under identifier PXD003075.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:26948580"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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