Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau

Abstract

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.

Department(s)

Mining Engineering

Comments

We thank Dr. Guy Surpris and Benjamin Morris-Eppolito for critical discussions. This study was supported by the award I01BX003527 and I21 BX003807 from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development (WX) and the Cure Alzheimer's Fund (WX). This publication was also made possible by funding from the DoD Congressionally Directed Medical Research Programs (CDMRP) for the Peer Reviewed Alzheimer's Research Program Convergence Science Research Award (PRARP-CSRA; AZ140109) and the research funds of the University of Missouri (ZG). The views expressed in this article are those of the authors and do not represent the views of the US Department of Veterans Affairs or the US Government.

Keywords and Phrases

Actin binding protein; Calcium calmodulin dependent protein kinase; Microtubule associated protein 5; Myelin basic protein; Neurofilament protein; Protein; Protein tag; Stathmin; Synaptotagmin I; Tau protein; Alzheimer disease; Animal experiment; Animal tissue; Article; Axon; Axonal injury; Bioinformatics; Blast injury; Brain; Brain cortex; Brain tissue; Controlled study; Cytoskeleton; Dendrite; Exocytosis; Histopathology; Liquid chromatography-mass spectrometry; Male; Mouse; Nerve degeneration; Nerve fiber degeneration; Neurofilament; Neurologic disease; Neuropsychological test; Nonhuman; Nucleotide sequence; Open field test; Pathogenesis; Priority journal; Protein analysis; Protein phosphorylation; Proteomics; signal transduction; Silver staining; Simple Neuroassessment of Asymmetric Impairment test; Substantia nigra; Synapse; Synapse vesicle; Traumatic brain injury

International Standard Serial Number (ISSN)

1387-2877

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2018 IOS Press, All rights reserved.

Publication Date

01 Oct 2018

PubMed ID

30347620

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