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TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury

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Abstract

Traumatic brain injury (TBI) has been recognized as an important risk factor for Alzheimer’s disease (AD). However, the molecular mechanisms by which TBI contributes to developing AD remain unclear. Here, we provide evidence that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). We observed that a single mild CHI is sufficient to exacerbate AD neuropathology and accelerate synaptic and cognitive deterioration in APP transgenic mice but repeated mild CHI are required to induce neuropathological changes and impairments in synaptic plasticity, spatial learning, and memory retention in wild-type animals. Importantly, these changes in animals exposed to a single or repeated mild CHI are alleviated by silencing of TDP-43 but reverted by rescue of the TDP-43 knockdown. Moreover, overexpression of TDP-43 in the hippocampus aggravates AD neuropathology and provokes cognitive impairment in APP transgenic mice, mimicking single mild CHI-induced changes. We further discovered that neuroinflammation triggered by TBI promotes NF-κB-mediated transcription and expression of TDP-43, which in turn stimulates tau phosphorylation and Aβ formation. Our findings suggest that excessive production of TDP-43 plays an important role in exacerbating AD neuropathology and in driving synaptic and cognitive declines following TBI.

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Data availability

Data supporting the findings of this manuscript are available the main text and the supplementary materials or from the corresponding authors upon request.

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Acknowledgements

We thank Dr. Bryan W. Luikart of Dartmouth Medical School for providing FUGW lentiviral vectors and Dr. Zhao-qian Teng for participating in the initial work of this project. This work was supported by National Institutes of Health grants R01NS076815, R01MH113535, and R01AG058621 (to C.C.) and by startup funds from UT Health San Antonio, Joe R. & Teresa Lozano Long School of Medicine (to C.C.).

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  1. Fei Gao, Mei Hu and Jian Zhang have contributed equally to this work.

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  1. Department of Cellular and Integrative Physiology, Center for Biomedical Neuroscience, Joe R. and Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, 78229, USA

    Fei Gao, Mei Hu, Jian Zhang, Jack Hashem & Chu Chen

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JZ and CC: conceived the project and designed the experiments; JZ, MH, FG and JH: performed the experiments and analyzed the data; CC: supervised the work and wrote the manuscript.

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Correspondence to Chu Chen.

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Gao, F., Hu, M., Zhang, J. et al. TDP-43 drives synaptic and cognitive deterioration following traumatic brain injury. Acta Neuropathol 144, 187–210 (2022). https://doi.org/10.1007/s00401-022-02449-w

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