The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

Jackson, Marcus; Chen, Shanyan; Nguyen, Thao Thi; Siedhoff, Heather R.; Balderrama, Ashley; Zuckerman, Amitai; Li, Runting; Greenlief, C. Michael; Cole, Gregory; Frautschy, Sally A.; Cui, Jiankun; Gu, Zezong

doi:10.3390/ijms25063338

Open AccessArticle

The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

by

Marcus Jackson

¹

,

Shanyan Chen

¹,

Thao Thi Nguyen

²

,

Heather R. Siedhoff

^1,3,

Ashley Balderrama

^1,3,

Amitai Zuckerman

¹,

Runting Li

^1,3,

C. Michael Greenlief

²

,

Gregory Cole

^4,5,

Sally A. Frautschy

^4,5

,

Jiankun Cui

^1,3 and

Zezong Gu

^1,3,*

¹

Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, USA

²

Charles W. Gehrke Proteomics Center, University of Missouri, Columbia, MO 65211, USA

³

Harry S. Truman Memorial Veterans’ Hospital Research Service, Columbia, MO 65201, USA

⁴

Geriatric Research Education and Clinical Center (GRECC), West Los Angeles Healthcare System, Los Angeles, CA 90073, USA

⁵

Departments of Neurology and Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2024, 25(6), 3338; https://doi.org/10.3390/ijms25063338

Submission received: 26 January 2024 / Revised: 5 March 2024 / Accepted: 5 March 2024 / Published: 15 March 2024

(This article belongs to the Special Issue Blast-Induced Neurotrauma: Molecular Mechanisms Supported by Comparative Experimental and Clinical Findings)

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Abstract

Blast-induced neurotrauma (BINT) is a pressing concern for veterans and civilians exposed to explosive devices. Affected personnel may have increased risk for long-term cognitive decline and developing tauopathies including Alzheimer’s disease-related disorders (ADRD) or frontal-temporal dementia (FTD). The goal of this study was to identify the effect of BINT on molecular networks and their modulation by mutant tau in transgenic (Tg) mice overexpressing the human tau P301L mutation (rTg4510) linked to FTD or non-carriers. The primary focus was on the phosphoproteome because of the prominent role of hyperphosphorylation in neurological disorders. Discrimination learning was assessed following injury in the subsequent 6 weeks, using the automated home-cage monitoring CognitionWall platform. At 40 days post injury, label-free phosphoproteomics was used to evaluate molecular networks in the frontal cortex of mice. Utilizing a weighted peptide co-expression network analysis (WpCNA) approach, we identified phosphopeptide networks tied to associative learning and mossy-fiber pathways and those which predicted learning outcomes. Phosphorylation levels in these networks were inversely related to learning and linked to synaptic dysfunction, cognitive decline, and dementia including Atp6v1a and Itsn1. Low-intensity blast (LIB) selectively increased pSer262tau in rTg4510, a site implicated in initiating tauopathy. Additionally, individual and group level analyses identified the Arhgap33 phosphopeptide as an indicator of BINT-induced cognitive impairment predominantly in rTg4510 mice. This study unveils novel interactions between ADRD genetic susceptibility, BINT, and cognitive decline, thus identifying dysregulated pathways as targets in potential precision-medicine focused therapeutics to alleviate the disease burden among those affected by BINT.

Keywords: low-intensity open-field blast; discrimination-learning index; phosphopeptides; label-free DIA-PASEF quantitative proteomics; phosphoproteomic profiling; WpCNA; eigenpeptides

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MDPI and ACS Style

Jackson, M.; Chen, S.; Nguyen, T.T.; Siedhoff, H.R.; Balderrama, A.; Zuckerman, A.; Li, R.; Greenlief, C.M.; Cole, G.; Frautschy, S.A.; et al. The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression. Int. J. Mol. Sci. 2024, 25, 3338. https://doi.org/10.3390/ijms25063338

AMA Style

Jackson M, Chen S, Nguyen TT, Siedhoff HR, Balderrama A, Zuckerman A, Li R, Greenlief CM, Cole G, Frautschy SA, et al. The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression. International Journal of Molecular Sciences. 2024; 25(6):3338. https://doi.org/10.3390/ijms25063338

Chicago/Turabian Style

Jackson, Marcus, Shanyan Chen, Thao Thi Nguyen, Heather R. Siedhoff, Ashley Balderrama, Amitai Zuckerman, Runting Li, C. Michael Greenlief, Gregory Cole, Sally A. Frautschy, and et al. 2024. "The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression" International Journal of Molecular Sciences 25, no. 6: 3338. https://doi.org/10.3390/ijms25063338

APA Style

Jackson, M., Chen, S., Nguyen, T. T., Siedhoff, H. R., Balderrama, A., Zuckerman, A., Li, R., Greenlief, C. M., Cole, G., Frautschy, S. A., Cui, J., & Gu, Z. (2024). The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression. International Journal of Molecular Sciences, 25(6), 3338. https://doi.org/10.3390/ijms25063338

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The Chronic Effects of a Single Low-Intensity Blast Exposure on Phosphoproteome Networks and Cognitive Function Influenced by Mutant Tau Overexpression

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