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Spinal Cord Injury Causes Prominent Tau Pathology Associated with Brain Post-Injury Sequela

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Abstract

Spinal cord injury (SCI) can result in significant neurological impairment and functional and cognitive deficits. It is well established that SCI results in focal neurodegeneration that gradually spreads to other cord areas. On the other hand, traumatic brain injury (TBI) is strongly associated with tau protein pathology and neurodegeneration that can spread in areas throughout the brain. Tau is a microtubule-associated protein abundant in neurons and whose abnormalities result in neuronal cell death. While SCI and TBI have been extensively studied, there is limited research on the relationship between SCI and brain tau pathology. As a result, in this study, we examined tau pathology in spinal cord and brain samples obtained from severe SCI mouse models at various time points. The effects of severe SCI on locomotor function, spatial memory, anxiety/risk-taking behavior were investigated. Immunostaining and immunoblotting confirmed a progressive increase in tau pathology in the spinal cord and brain areas. Moreover, we used electron microscopy to examine brain samples and observed disrupted mitochondria and microtubule structure following SCI. SCI resulted in motor dysfunction, memory impairment, and abnormal risk-taking behavior. Notably, eliminating pathogenic cis P-tau via systemic administration of appropriate monoclonal antibodies restored SCI’s pathological and functional consequences. Thus, our findings suggest that SCI causes severe tauopathy that spreads to brain areas, indicating brain dysfunction. Additionally, tau immunotherapy with an anti-cis P-tau antibody could suppress pathogenic outcomes in SCI mouse models, with significant clinical implications for SCI patients.

Graphical abstract

SCI induces profound pathogenic cis p-tau, which diffuses into the brain through CSF, resulting in brain neurodegeneration and cognitive decline.

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Data availability

The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

SCI:

Spinal cord injury

CSF:

Cerebrospinal fluid

TBI:

Traumatic brain injury

MTs:

Microtubules

CTE:

Chronic traumatic encephalography

cis P-tau:

cis PThr231-tau

AD:

Alzheimer’s disease

Pin1:

Peptidyl-prolyl cis/trans isomerase

Cis mAb:

cis P-tau monoclonal antibody

sSCI:

Severe SCI

NIH:

National Institute of Health

SC:

Subcutaneously

BMS:

The Basso mouse scale

OF:

Open-field

IP:

Intraperitoneal

TEM:

Transmission electron microscopy

EPM:

Elevated plus-maze

ROI:

Region of interest

ANOVA:

Analysis of variance

SD:

Standard deviation

ssTBI:

Single severe TBI

rmTBI:

Repetitive mild TBI

LTP:

Long-term potentiation

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Funding

The grant of this study was provided by Neurosciences Research Center of Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Council for Stem Cell Sciences and Technologies, Tehran, Iran (Grant number: 11/35721); and grant #1397-A-5443 from Royan Institute for Stem Cell Biology & Technology, Tehran, Iran.

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Authors and Affiliations

  1. Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran

    Elnaz Nakhjiri

  2. Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Shaqayeq Roqanian & Koorosh Shahpasand

  3. Department of Neuroscience and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Hamid Soltani Zangbar

  4. Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

    Manuchehr Seyedi Vafaee

  5. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Daryoush Mohammadnejad & Parviz Shahabi

  6. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

    Shahin Ahmadian

  7. Department of Biological Sciences, Islamic Azad University, Tehran, Iran

    Selva Zamanzadeh

  8. Department of Biology, Roudehen Islamic Azad University, Roudehen, Iran

    Ehsan Ehsani

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  1. Elnaz Nakhjiri
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  5. Daryoush Mohammadnejad
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  6. Shahin Ahmadian
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  7. Selva Zamanzadeh
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  8. Ehsan Ehsani
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  9. Parviz Shahabi
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  10. Koorosh Shahpasand
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Contributions

All authors contributed to the study conception and design. Elnaz Nakhjiri expressed the idea of the article and performed the literature search. Material preparation, data collection and analysis were performed by Selva Zamanzadeh, Ehsan Ehsani, Hamid Soltani Zangbar, Shaqayeq Roqanian, Daryoush Mohammadnejad and Shahin Ahmadian. The first draft of the manuscript was written by Elnaz Nakhjiri, Koorosh Shahpasand and Parviz Shahabi. All authors edited the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Parviz Shahabi or Koorosh Shahpasand.

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This study was conducted following the Declaration of Helsinki’s principles. The Tabriz University of Medical Sciences Ethics Committee approved this study (Code of ethics: IR.TBZMED.VCR.REC.1398.067).

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The authors have no relevant financial or non-financial interests to disclose.

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Nakhjiri, E., Roqanian, S., Zangbar, H.S. et al. Spinal Cord Injury Causes Prominent Tau Pathology Associated with Brain Post-Injury Sequela. Mol Neurobiol 59, 4197–4208 (2022). https://doi.org/10.1007/s12035-022-02843-1

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  • DOI: https://doi.org/10.1007/s12035-022-02843-1

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