Dataset Information

BACE1 inhibition induces a specific cerebrospinal fluid ?-amyloid pattern that identifies drug effects in the central nervous system.

ABSTRACT: BACE1 is a key enzyme for amyloid-? (A?) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal A? metabolism, inducing a unique pattern of secreted A? peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in A?1-40 and A?1-42, treatment also changed the relative levels of several other A? isoforms. In particular A?1-34 decreased, while A?5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in A?1-40 and A?1-42. The effects on A?5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF A? pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.

SUBMITTER: Mattsson N

PROVIDER: S-EPMC3273469 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.

Mattsson Niklas N Rajendran Lawrence L Zetterberg Henrik H Gustavsson Mikael M Andreasson Ulf U Olsson Maria M Brinkmalm Gunnar G Lundkvist Johan J Jacobson Laura H LH Perrot Ludovic L Neumann Ulf U Borghys Herman H Mercken Marc M Dhuyvetter Deborah D Jeppsson Fredrik F Blennow Kaj K Portelius Erik E

PloS one 20120206 2

BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1- ...[more]

PMID: 22328928

Similar Datasets

Project description:Importance:Recent studies found that the concentration of amyloid-? (A?) fluctuates with the sleep-wake cycle. Although the amplitude of this day/night pattern attenuates with age and amyloid deposition, to our knowledge, the association of A? kinetics (ie, production, turnover, and clearance) with this oscillation has not been studied. Objective:To determine the association between A? kinetics, age, amyloid levels, and the A? day/night pattern in humans. Design, Setting, and Participants:We measured A? concentrations and kinetics in 77 adults aged 60 to 87 years with and without amyloid deposition by a novel precise mass spectrometry method at the Washington University School of Medicine in St Louis, Missouri. We compared findings of 2 orthogonal methods, enzyme-linked immunosorbent assay and mass spectrometry, to validate the day/night patterns and determine more precise estimates of the cosinor parameters. In vivo labeling of central nervous system proteins with stable isotopically labeled leucine was performed, and kinetics of A?40 and A?42 were measured. Interventions:Serial cerebrospinal fluid collection via indwelling lumbar catheter over 36 to 48 hours before, during, and after in vivo labeling, with a 9-hour primed constant infusion of 13C6-leucine. Main Outcomes and Measures:The amplitude, linear increase, and other cosinor measures of each participant's serial cerebrospinal fluid A? concentrations and A? turnover rates. Results:Of the 77 participants studied, 46 (59.7%) were men, and the mean (range) age was 72.6 (60.4-87.7) years. Day/night patterns in A? concentrations were more sharply defined by the precise mass spectrometry method than by enzyme-linked immunosorbent assay (mean difference of SD of residuals: A?40, -7.42 pM; P?<?.001; A?42, -3.72 pM; P?<?.001). Amyloid deposition diminished day/night amplitude and linear increase of A?42 but not of A?40. Increased age diminished day/night amplitude of both A?40 and A?42. After controlling for amyloid deposition, amplitude of A?40 was positively associated with production rates (r?=?0.42; P?<?.001), while the linear rise was associated with turnover rates (r?=?0.28; P?<?.05). The amplitude and linear rise of A?42 were both associated with turnover (r?=?-0.38; P?<?.001) and production (r?=?0.238; P?<?.05) rates. Conclusions and Relevance:Amyloid deposition is associated with premature loss of normal A?42 day/night patterns in older adults, suggesting the previously reported effects of age and amyloid on A?42 amplitude at least partially affect each other. Production and turnover rates suggest that day/night A? patterns are modulated by both production and clearance mechanisms active in sleep-wake cycles and that amyloid deposition may impair normal circadian patterns. These findings may be important for the designs of future secondary prevention trials for Alzheimer disease.

Dataset Information

BACE1 inhibition induces a specific cerebrospinal fluid ?-amyloid pattern that identifies drug effects in the central nervous system.

Publications

BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets