Traumatic Brain Injury Induces Tau Aggregation and Spreading.

George Edwards,Claudio Soto,Pramod K Dash,Jing Zhao,Ines Moreno-Gonzalez

doi:10.1089/neu.2018.6348

Abstract

The misfolding and aggregation of tau protein into neurofibrillary tangles is the main underlying hallmark of tauopathies. Most tauopathies have a sporadic origin and can be associated with multiple risk factors. Traumatic brain injury (TBI) has been suggested as a risk factor for tauopathies by triggering disease onset and facilitating its progression. Several studies indicate that TBI seems to be a risk factor to development of Alzheimer disease and chronic traumatic encephalopathy, because there is a relationship of TBI severity and propensity to development of these illnesses. In this study, we evaluated whether moderate to severe TBI can trigger the initial formation of pathological tau that would induce the development of the pathology throughout the brain. To this end, we subjected tau transgenic mice to TBI and assessed tau phosphorylation and aggregation pattern to create a spatial heat map of tau deposition and spreading in the brain. Our results suggest that brain injured tau transgenic mice have an accelerated tau pathology in different brain regions that increases over time compared with sham mice. The appearance of pathological tau occurs in regions distant to the injury area that are connected synaptically, suggesting dissemination of tau aggregates. Overall, this work posits TBI as a risk factor for tauopathies through the induction of tau hyperphosphorylation and aggregation.

Highlights

Tau is a microtubule associated binding protein that, under normal physiological conditions, provides cytoskeletal support allowing axonal transport, among other functions
Hyperphosphorylated tau aggregates generate neurofibrillary tangles (NFTs) that are considered the pathological hallmark of tauopathies including Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and frontal-temporal dementia (FTD), among others.[2,3,4,5]
In CTE, tau is found around small vessels at the depths of sulci in the cerebral cortex, superficial layers of adjacent cortex, frontal, insular, temporal and parietal cortices, and amygdala, hippocampus, and entorhinal cortex, and ptau pathology is found widespread in the entire brain.[9]

Summary

Introduction

Tau is a microtubule associated binding protein that, under normal physiological conditions, provides cytoskeletal support allowing axonal transport, among other functions. Triggers microtubule-bound tau to be released.[1,2] Hyperphosphorylated tau (ptau) aggregates generate neurofibrillary tangles (NFTs) that are considered the pathological hallmark of tauopathies including Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and frontal-temporal dementia (FTD), among others.[2,3,4,5]. In these tauopathies, tau follows an explicit and predictable spatiotemporal pattern of deposition. Neuropathological Braak staging of tau accumulation in AD progresses from transentorhinal/locus coeruleus (stages I/II), limbic (stages III/IV), and isocortical (stages V/VI).[6,7,8] In CTE, tau is found around small vessels at the depths of sulci in the cerebral cortex (stage I), superficial layers of adjacent cortex (stage II), frontal, insular, temporal and parietal cortices, and amygdala, hippocampus, and entorhinal cortex (stage III), and ptau pathology is found widespread in the entire brain (stage IV).[9]

Methods

Results

Conclusion