ArticleAlzheimer's research & therapy2015
APLP1 as a cerebrospinal fluid biomarker for γ-secretase modulator treatment.
Article in Alzheimer's research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 10 citations in OpenAlex.
- Wide-Ranging Effects on the Brain Proteome in a Transgenic Mouse Model of Alzheimer's Disease Following Treatment with a Brain-Targeting Somatostatin Peptide.ACS chemical neuroscience · 2021Article
- A comprehensive systematic review of CSF proteins and peptides that define Alzheimer's disease.Clinical proteomics · 2020Review
- Article
- Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus.Fluids and barriers of the CNS · 2016Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionAlzheimer's disease brains are characterized by extracellular plaques containing the aggregated amyloid β42 (Aβ42) peptide and intraneuronal tangles containing hyperphosphorylated tau. Aβ42 is produced by sequential processing of the amyloid precursor protein (APP) by β-secretase followed by γ-secretase. Substantial efforts have been put into developing pharmaceuticals preventing the production or increasing the clearance of Aβ42. However, treatments inhibiting γ-secretase have proven disappointing due to off-target effects. To circumvent these effects, γ-secretase modulators (GSMs) have been developed, which rather than inhibiting γ-secretase shift its preference into producing less aggregation-prone shorter Aβ peptides. Belonging to the same family of proteins as APP, amyloid-like protein 1 (APLP1) is also a substrate for γ-secretase. Herein we investigated whether the GSM E2012 affects APLP1 processing in the central nervous system by measuring APLP1 peptide levels in cerebrospinal fluid (CSF) before and after E2012 treatment in dogs.
methodsAn in-house monoclonal APLP1 antibody, AP1, was produced and utilized for immunopurification of APLP1 from human and dog CSF in a hybrid immuno-affinity mass spectrometric method. Seven dogs received a single dose of 20 or 80 mg/kg of E2012 in a randomized cross-over design and CSF was collected prior to and 4, 8 and 24 hours after dosing.
resultsWe have identified 14 CSF APLP1 peptides in humans and 12 CSF APLP1 peptides in dogs. Of these, seven were reproducibly detectable in dogs who received E2012. We found a dose-dependent relative increase of the CSF peptides APLP1β17, 1β18 and 1β28 accompanied with a decrease of 1β25 and 1β27 in response to E2012 treatment. All peptides reverted to baseline over the time of sample collection.
conclusionWe show an in vivo effect of the GSM E2012 on the processing of APLP1 which is measurable in CSF. These data suggest that APLP1 peptides may be used as biomarkers to monitor drug effects of GSMs on γ-secretase processing in clinical trials. However, this requires further investigation in larger cohorts, including studies in man.
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