"Short-term Treatment with Dabigatran Alters Protein Expression Pattern" by Jaclyn Iannucci, Shelby L. Johnson et al.

Biomedical and Pharmaceutical Sciences Faculty Publications

Title

Short-term Treatment with Dabigatran Alters Protein Expression Patterns in a Late-Stage Tau-Based Alzheimer's Disease Mouse Model

Authors

Jaclyn Iannucci
Shelby L. Johnson
Mark Majchrzak, University of Rhode IslandFollow
Benjamin J. Barlock
Fatemeh Akhlaghi, University of Rhode IslandFollow
Navindra P. Seeram, University of Rhode IslandFollow
Abhik Sen
Paula Grammas

Document Type

Article

Date of Original Version

11-2020

Abstract

Proteins that regulate the coagulation cascade, including thrombin, are elevated in the brains of Alzheimer's disease (AD) patients. While studies using amyloid-based AD transgenic mouse models have implicated thrombin as a protein of interest, the role of thrombin in tau-based animal models has not been explored. The current study aims to determine how inhibiting thrombin could alter oxidative stress, inflammation, and AD-related proteins in a tau-based mouse model, the Tg4510. Aged Tg4510 mice were treated with the direct thrombin inhibitor dabigatran or vehicle for 7 days, brains collected, and western blot and data-independent proteomics using mass spectrometry with SWATH-MS acquisition performed to evaluate proteins related to oxidative stress, intracellular signaling, inflammation, and AD pathology. Dabigatran reduced iNOS, NOX4, and phosphorylation of tau (S396, S416). Additionally, dabigatran treatment increased expression of several signaling proteins related to cell survival and synaptic function. Increasing evidence supports a chronic procoagulant state in AD, highlighting a possible pathogenic role for thrombin. Our data demonstrate that inhibiting thrombin produces alterations in the expression of proteins involved in oxidative stress, inflammation, and AD-related pathology, suggesting that thrombin-mediated signaling affects multiple AD-related pathways providing a potential future therapeutic target.

Citation/Publisher Attribution

Iannucci J, Johnson SL, Majchrzak M, Barlock BJ, Akhlaghi F, Seeram NP, Sen A, Grammas P. Short-term treatment with dabigatran alters protein expression patterns in a late-stage tau-based Alzheimer's disease mouse model. Biochem Biophys Rep. 2020 Nov 19;24:100862. doi: 10.1016/j.bbrep.2020.100862. PMID: 33294639; PMCID: PMC7689047.