Traumatic Brain Injury Induces Tau Aggregation and Spreading

George Edwards 3rd, Jing Zhao, Pramod K Dash, Claudio Soto, Ines Moreno-Gonzalez, George Edwards 3rd, Jing Zhao, Pramod K Dash, Claudio Soto, Ines Moreno-Gonzalez

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.

Keywords: Alzheimer disease; chronic traumatic encephalopathy; risk factor; tau aggregation; traumatic brain injury.

Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
Tau aggregation is induced one day after traumatic brain injury (TBI). Tau hyperphosphorylation was assessed in brain homogenates and coronal tissue sections in three-month-old P301S TBI and sham induced mice one day after the event. (A) Representative bright field microscopy images of AT8 immunoreactivity in TBI and sham mice brain sections. (B) The AT8 burden quantification was obtained by analyzing the percentage of the area reactive with AT8 antibody in relation to the total area analyzed in the cortex/amygdala, hippocampal area, and brainstem. Statistical analysis was performed by Student t test or Mann-Whitney test for the ipsilateral (Ipsi) and contralateral (Contra) areas of impact as well as overall brain region. Ipsilateral and contralateral hippocampus quantifications were analyzed by Mann-Whitney test. (C) Semi-quantitative evaluation (lowest [0] to highest [5]) of tau deposition is captured in the heat map at different distance from the impacted area. The star denotes the estimated placement of impact. (D,E) Insoluble tau levels were evaluated by serial extraction and enzyme-linked immunosorbent assay performed in the formic acid fraction of the brains. Graphs in panels B, D, and E show the mean ± standard error of the mean of the n = 5 animals analyzed per group. Scale bar: 100 μm. *p < 0.05, **p < 0.01, ***p < 0.001.
FIG. 2.
FIG. 2.
Spatial pattern and burden of pathological tau one week after traumatic brain injury (TBI). The P301S mice having either a TBI or sham surgery were assessed for tau aggregate formation and spreading by AT8 immunostaining. (A) Representative images of the TBI and sham animals using AT8 antibody are displayed. (B) The AT8 burden was evaluated in the cortex, hippocampal area, and brainstem in overall, ipsilateral (Ipsi), and contralateral (Contra) side of impact. Ipsilateral and contralateral hippocampus were evaluated by Mann-Whitney test, while all other data underwent Student t test. (C) Four coronal areas per animal were assessed to re-create a heat map to navigate tau spreading after TBI. Heat map scale: lowest (0) to highest (5) score. The star denotes the estimated placement of impact. Scale bar: 100 μm. *p < 0.05, **p < 0.01.
FIG. 3.
FIG. 3.
Tau aggregation is significantly increased two months after traumatic brain injury (TBI) injury. (A) Illustrative microphotography of AT8 immunopositive staining visually displayed growing pathologic tau aggregation. (B) The AT8 burden quantification in the overall, ipsilateral (Ipsi), and contralateral (Contra) impacted area in the three main brain regions analyzed. Ipsilateral cortex and Contra hippocampus were evaluated by Mann-Whitney test, while all other statistical analysis was performed by Student t test. (C) The spatial heat map revealed increasing tau burden and presence of pathogenic tau aggregates in multiple areas in TBI-induced mice having more aggressive pathology compared with sham mice. Scale bar: 100 μm. Heat map scale: lowest (0) to highest (5) score. The star denotes the estimated placement of impact. *p < 0.05, **p < 0.01.
FIG. 4.
FIG. 4.
Traumatic brain injury (TBI) promotes behavior impairment in transgenic tau mice in the chronic stage of injury. Barnes maze test was performed on P301S TBI, P301S sham, and wild-type (WT) littermate TBI mice six months after controlled cortical impact injury. The P301S TBI mice exhibited attenuated learning and memory capabilities observed by the learning curve (A) and long term memory assessment (B) *p < 0.05, **p < 0.01, ***p < 0.001.
FIG. 5.
FIG. 5.
Robust tau pathology six months after traumatic brain injury (TBI). (A) Example AT8 microscope images illustrate substantial tau pathology in TBI mice six months after injury compared with age-matched sham mice. (B) The AT8 burden quantification shows a significant overall increase of tau deposition in TBI mice compared with sham mice in the ipsilateral (Ipsi), contralateral (Contra), and overall cortex and hippocampal area. Statistics for brainstem were calculated by Mann-Whitney test, while all other were performed by Student t test. (C) The AT8 burden scores exhibited in a spatial heat map of four rostrocaudal areas in TBI versus sham mice. Heat map scale: lowest (0) to highest (5) score. Star denotes the estimated placement of impact. Scale bar: 100 μm. *p < 0.05.
FIG. 6.
FIG. 6.
Altered tropism of tau deposition after traumatic brain injury (TBI). Representative figures of pathological tau deposition as evaluated by AT8 immunohistochemistry in hippocampus, cortex, and cerebellar lobes in mice six months after TBI. Age-matched P301S sham animals revealed very low detectability using AT8 at the different times analyzed. Scale bar: 100 μm; insets: 30 μm. CA1, cornu ammonis 1 area; cc, corpus callosum; DG, dentate gyrus; Ctx, cortex; Hp, hippocampus; ml, molecular layer, gl, granular layer; wm, white matter.
FIG. 7.
FIG. 7.
Traumatic brain injury (TBI)-induced tau aggregates fold-change summary. The AT8 burden fold-change is represented in the overall, ipsilateral (Ipsi) and contralateral (Contra) side of impact in the hippocampal area (HPa), cortex/amygdala, and brainstem (BS) in relation to the respective brain areas rostrocaudally to the impacted side in TBI versus sham induced mice. The colored scale exhibits the lowest to highest fold change compared with sham brains. The fold-change values displayed in red were analyzed by Mann-Whitney test while all other data analysis was performed by Student t test. The values below the fold change display the lower to upper 95% confidence interval of the mean of the TBI (top) and sham (bottom) groups. *p < 0.05.

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