Identification of potential biomarkers related to mesenchymal stem cell response in patients with Alzheimer’s disease

Abstract

Abstract Background Preclinical studies showed that mesenchymal stem cells (MSCs) ameliorate tau phosphorylation, amyloid-beta accumulation, and inflammation in Alzheimer’s disease (AD) mouse models via secretion of neurotrophic factors and cytokines. We aimed to identify CSF biomarkers that can be used to predict or monitor the response to MSCs in patients with AD. Methods AD patients were injected with human umbilical cord blood-MSCs (n = 22) or placebo (n = 12). The cerebrospinal fluid (CSF) samples were collected at baseline, one day after the first injection, and one day after the third injection. The patients injected with MSCs were classified into good responder (GR) or poor responder (PR) groups based on the rate of changes in the ratio of total-tau and phosphorylated-tau in the CSF. We selected three typical participants in each group, and their CSF protein levels were analyzed using liquid chromatography/tandem mass spectrometry (LC–MS/MS). Results In the LC–MS/MS analysis, 1,667 proteins were identified. Eleven proteins showed significant differences between the typical GR and PR at baseline. Based on their significance level and known functions, two proteins, reticulocalbin-3 (RCN3) and follistatin-related protein 3 (FSTL3), were selected as potential biomarkers to predict MSC response. A total of 173 proteins showed significant change one day after the third injection compared to the baseline in typical GR. We excluded 45 proteins that showed significant change after the third injection compared to the baseline in the typical PR. Based on their significance level and known function, four proteins, scrapie-responsive protein 1 (SCRG1), neural proliferation differentiation and control protein (NPDC1), apolipoprotein E (ApoE), and cystatin C (CysC), were selected as potential biomarker to monitor MSC response. Additionally, functional analysis revealed that the increased CSF proteins after the third injection compared to the baseline in the typical GR were associated with synaptogenesis. Conclusions This study identified two proteins (RCN3 and FSTL3) that may be potential biomarkers for predicting MSC response and four proteins (SCRG1, NPDC1, ApoE, CysC) that may be potential biomarkers for monitoring MSC response in patients with AD. Further studies are needed to validate our results. Trial registration Clinical Trials.gov, NCT02054208. Registered on 4 February 2014. Samsung Medical Center IRB File No.2017-04-025. Registered on 20 June 2017.