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Uncover possible mechanism of sodium benzoate in treating patients with AD using label free quantitative serum proteomics

ABSTRACT: AD is a progressive neurodegenerative disorder characterized by a decline in memory that ultimately leads to dementia. N-methyl-D-aspartate receptors are crucial components of brain function involved in memory and neurotransmission. Currently, targeting NMDARs with medication has shown potential in providing dementia-related benefits for AD patients. Sodium benzoate is a promising NMDAR enhancer that reduces oxidative stress, thereby offering neuroprotection. Sodium benzoate has been proved as a novel, safe and efficient therapy to patients with AD. However, in addition to the role as an NMDAR enhancer, other mechanism of sodium benzoate is still unclear. To uncover possible mechanism of sodium benzoate in treating patients with Alzheimer's disease, in this study, serum samples from AD patients with sodium benzoate treatment or a placebo were analyzed using label free quantitative proteomics. The serum proteins were separated into 24 fractions using immobilized pH gradient. Each subfraction was individually digested with trypsin and then subjected to nanoLC-MS/MS to analyze the proteome of all patients. There were 837 and 807 protein groups identified in the benzoate-treatment group and the placebo group, respectively. Our result shows that sodium benzoate had the most significant effect in the pathway of complement and coagulation cascades, disease-gene associations of amyloidosis, the biological process of immune responses, and lipid metabolic process. TTR, FGA, HP, ApoB, FGB APOE and ApoA1 were found to be the hub proteins of the protein-protein interaction networks. Our results showed that sodium benzoate could affect some important pathways which play key roles in the pathogenesis of AD.

INSTRUMENT(S): impact

ORGANISM(S): Human

SUBMITTER: Chao-Jung Chen

PROVIDER: MSV000092141 | MassIVE | Sun Jun 11 21:04:00 BST 2023

REPOSITORIES: MassIVE

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Project description:Lockwood2006 - AlzheimersDisease PBPK model A mathematical model to predict the effectiveness of CI-1017 (muscarinic agonist) for Alzheimer's disease by evaluating changes in ADAS-cog score. This model is described in the article: Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease. Lockwood P, Ewy W, Hermann D, Holford N. Pharm. Res. 2006 Sep; 23(9): 2050-2059 Abstract: OBJECTIVE: Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials. MATERIALS AND METHODS: A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025). RESULTS: A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability. CONCLUSION: CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial. This model is hosted on BioModels Database and identified by: BIOMD0000000673. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Uncover possible mechanism of sodium benzoate in treating patients with AD using label free quantitative serum proteomics

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