Short-term treatment with dabigatran alters protein expression patterns in a late-stage tau-based Alzheimer's disease mouse model

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

doi:10.1016/j.bbrep.2020.100862

Jaclyn Iannucci, Shelby L Johnson + Show 6 more

Open Access

https://doi.org/10.1016/j.bbrep.2020.100862

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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.

Highlights

Cardiovascular disease and cardiovascular risk factors (CVRFs) are strongly associated with an increased risk of developing dementia, Alzheimer’s disease (AD) [1]
Increasing evidence has shown that thrombin, and thrombin-related proteins are elevated in the brains of AD patients [11]
Oxidative stress resulting from generation of high levels of reactive oxygen species (ROS) in AD is associated with neuron injury, Aβ accumulation, and tau phosphory lation [21,22]

Summary

Introduction

Cardiovascular disease and cardiovascular risk factors (CVRFs) are strongly associated with an increased risk of developing dementia, Alzheimer’s disease (AD) [1]. While the connection be tween CVRFs and AD is well-documented, mechanisms whereby these risk factors confer elevated AD risk have not been delineated. The multifunc tional protease thrombin is implicated in the development of athero sclerosis and diabetes, and more recently suggested as a novel mediator in AD [2,3]. Recent evidence indicates that coagu lation proteins, including thrombin, mediate oxidative stress and neuroinflammation, invariant features of neurodegenerative diseases [5]. Thrombin increases NADPH-dependent superoxide anion and hydrogen peroxide production, and injures neurons via microglial release of nitric oxide (NO) [6,7]. In a primarily amyloid-based AD mouse model (3xTgAD), we have previously shown that administration of the thrombin inhibitor dabigatran significantly decreases expression of reactive oxygen species (ROS) and inflammatory proteins in these mice [8]

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