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?-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces A?5-X peptides through alternative amyloid precursor protein cleavage.

ABSTRACT: The ?-secretase enzyme, ?-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in ?-amyloid (A?) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory A? biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of A?1-34 together with increased A?5-40, suggesting that these A? species may be novel pharmacodynamic biomarkers in clinical trials. We have now examined whether the same holds true in humans.In an investigator-blind, placebo-controlled and randomized study, healthy subjects (n =18) were randomly assigned to receive a single dose of 30 mg of LY2811376 (n =6), 90 mg of LY2811376 (n =6), or placebo (n =6). We used hybrid immunoaffinity-mass spectrometry (HI-MS) and enzyme-linked immunosorbent assays to monitor a variety of A? peptides.Here, we demonstrate dose-dependent changes in cerebrospinal fluid (CSF) A?1-34, A?5-40 and A?5-X after treatment with the BACE1-inhibitor LY2811376. A?5-40 and A?5-X increased dose-dependently, as reflected by two independent methods, while A?1-34 dose-dependently decreased.Using HI-MS for the first time in a study where subjects have been treated with a BACE inhibitor, we confirm that CSF A?1-34 may be useful in clinical trials on BACE1 inhibitors to monitor target engagement. Since it is less hydrophobic than longer A? species, it is less susceptible to preanalytical confounding factors and may thus be a more stable marker. By independent measurement techniques, we also show that BACE1 inhibition in humans is associated with APP-processing into N-terminally truncated A? peptides via a BACE1-independent pathway.ClinicalTrials.gov NCT00838084. Registered: First received: January 23, 2009, Last updated: July 14, 2009, Last verified: July 2009.

SUBMITTER: Portelius E

PROVIDER: S-EPMC4233234 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage.

Portelius Erik E Dean Robert A RA Andreasson Ulf U Mattsson Niklas N Westerlund Anni A Olsson Maria M Demattos Ronald Bradley RB Racke Margaret M MM Zetterberg Henrik H May Patrick C PC Blennow Kaj K

Alzheimer's research & therapy 20141117 5-8

<h4>Introduction</h4>The β-secretase enzyme, β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), cleaves amyloid precursor protein (APP) in the first step in β-amyloid (Aβ) peptide production. Thus, BACE1 is a key target for candidate disease-modifying treatment of Alzheimer's disease. In a previous exploratory Aβ biomarker study, we found that BACE1 inhibitor treatment resulted in decreased levels of Aβ1-34 together with increased Aβ5-40, suggesting that these Aβ species may be novel ph ...[more]

PMID: 25404952

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Project description:Cerebrospinal fluid (CSF) β-site amyloid precursor protein cleaving enzyme 1 (BACE1), neurogranin and the neurogranin/BACE1 ratio are proposed markers for Alzheimer's disease. BACE1 is also a drug target. However, CSF levels may differ between early-stage amyloid plaque formation (A) and later stage downstream tau-tangle pathology (T) and neurodegeneration (N) and may be expressed as an A/T/N stage (e.g. A+/T-/N or A+/T+/N+). Whether BACE1 and neurogranin levels are persistent traits or change with disease progression is unknown. The aim of this study was to investigate whether CSF neurogranin and BACE1 concentrations differ between A/T/N stages, whether these change over time and correlate with memory decline. This may have implications for patient selection in future trials. We used CSF markers to determine A/T/N stage using amyloid beta42/40 ratio, p-tau181 and total-tau respectively in predementia Alzheimer's disease cases (n = 176) [including cases that progressed to dementia (n = 10)] and controls (n = 74) from the Norwegian Dementia Disease Initiation cohort. We selected cases at the presumed early (A+/T-/N-, n = 86) and late stages (A+/T+/N+, n = 90) of the Alzheimer's disease continuum and controlled with normal markers (A-/T-/N-, n = 74). A subset of subjects in all A/T/N groups underwent repeat CSF sampling at approximately 2-year intervals up to 6 years from baseline. Using linear mixed models, longitudinal measurements of CSF BACE1 and neurogranin levels in A+/T-/N- and A+/T+/N+ as compared to A-/T-/N- healthy controls were performed. Next, we measured changes in CSF BACE1 and neurogranin levels in cases that progressed from A-/T-/N- to A+/T-/N- (n = 12), from A+/T-/N- to A+/T or N+ (n = 12), remained stable A+/T-/N- (n = 26), remained stable A+/T+/N+ (n = 28) compared with controls remaining stable A-/T-/N- (n = 33). Lastly, associations between these markers and memory decline were assessed. Compared with A-/T-/N- healthy controls, neurogranin was unaltered in A+/T-/N- (n.s.) but higher in A+/T+/N+ (P < 0.0001). In contrast, BACE1 was lower in A+/T-/N- (P < 0.05) and higher in A+/T+/N+ (P < 0.0001). The neurogranin/BACE1 ratio was increased in both A+/T-/N- (P < 0.05) and A+/T+/N+ (P < 0.0001) groups as compared to A-/T-/N- healthy controls and was more strongly associated with memory decline (b = -0.29, P = 0.0006) than neurogranin (b = -0.20, P = 0.002) and BACE1 (b = -0.13, P = 0.046). Neurogranin and BACE1 level differences remained stable over time not only within A/T/N groups but also in patients progressing to more pathological A/T/N stages (e.g. progressing from A+/T-/N- to A + T or N+) and in cases progressing to dementia. Our results suggest that neurogranin and BACE1 levels may differentiate pathomechanistic Alzheimer's disease subgroups, putatively with different options for treatment.

Dataset Information

?-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces A?5-X peptides through alternative amyloid precursor protein cleavage.

Publications

β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage.

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