Repetitive Traumatic Brain Injury Causes Neuroinflammation before Tau Pathology in Adolescent P301S Mice.

Saef Izzy,Limin Wu,Gina Jin,Michael J Whalen,Sevda Lule,Joon Yong Chung,Liza M Morsett,Ali Alquraini,Joseph El Khoury,Taha Yahya,Aliyah Sarro-Schwartz,Suzanne E Hickman,Alexander Brown-Whalen

doi:10.3390/ijms22020907

Abstract

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

Highlights

Concussions continue to be a prominent public health concern, with an estimated1.6–3.8 million cases annually in the United States [1]
Chronic neuroinflammation resulting from the interactions of microglial scavenger and Toll-like receptors with noxious stimuli such as β-amyloid or lipopolysaccharide leads to the generation of neurotoxic substances and subsequently contribute to the pathophysiology of neurodegenerative disorders [34,35,36,37,38,39]. The impact of both Repetitive Closed-Head Injury (rCHI) and p-tau pathology on neuroinflammation and behavioral outcomes in adolescent mice remain poorly understood. To address this knowledge gap, we explored the relationship between adolescent concussion, neuroinflammation, and tauopathy using adolescent P301S transgenic mice that harbor a mutant form of the human microtubule-associated protein tau (MAPT) and exhibit similar tau pathology to human tauopathies [40,41]
AT8 staining was detected in the cell body and apical dendrites of neurons in the cortex, but not in the hippocampus, of both sham and injured groups of P301S mice (Figure 1a). rCHI did not significantly increase cortical tau phosphorylation in injured vs. sham P301S mice as measured by percentage surface area stained by AT8 (Figure 1e)

Summary

Introduction

Concussions continue to be a prominent public health concern, with an estimated1.6–3.8 million cases annually in the United States [1]. The long-term cognitive outcomes of repetitive concussive head injuries remain disputed, but there have been numerous epidemiological and neuropathological reports of an association with cognitive decline and neurodegenerative disease including chronic traumatic encephalopathy (CTE) [3,4,5,6]. Concussion in young athletes may increase the risk of chronic cognitive dysfunction compared to their adult counterparts [7]. Such concerns, coupled with the popularity of youth participation in contact sports, have made adolescent traumatic brain injury (TBI) a central focus of public attention [3,4,5,6].

Objectives

Methods

Results

Conclusion