Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Koren, Shon A.; Hamm, Matthew J.; Cloyd, Ryan; Fontaine, Sarah N.; Chishti, Emad; Lanzillotta, Chiara; Rodriguez-Rivera, Jennifer; Ingram, Alexandria; Bell, Michelle; Galvis-Escobar, Sara M.; Zulia, Nicholas; Di Domenico, Fabio; Duong, Duc; Seyfried, Nicholas T.; Powell, David; Vandsburger, Moriel; Frolinger, Tal; Hartz, Anika M. S.; Koren, John; Axten, Jeffrey M.; Laping, Nicholas J.; Abisambra, Jose F.

doi:10.3390/ijms22031186

Open AccessArticle

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

by

Shon A. Koren

¹

,

Matthew J. Hamm

¹,

Ryan Cloyd

²,

Sarah N. Fontaine

²,

Emad Chishti

²,

Chiara Lanzillotta

³

,

Jennifer Rodriguez-Rivera

²,

Alexandria Ingram

²,

Michelle Bell

²,

Sara M. Galvis-Escobar

¹,

Nicholas Zulia

¹,

Fabio Di Domenico

³

,

Duc Duong

⁴,

Nicholas T. Seyfried

⁴

,

David Powell

⁵,

Moriel Vandsburger

⁶,

Tal Frolinger

⁷,

Anika M. S. Hartz

²,

John Koren III

¹,

Jeffrey M. Axten

⁸

,

Nicholas J. Laping

⁸ and

Jose F. Abisambra

^1,*

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¹

Department of Neuroscience & Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32669, USA

²

Sanders Brown Center on Aging & Department of Physiology, University of Kentucky, Lexington, KY 40504, USA

³

Department of Biochemical Sciences, Sapienza University of Rome, Piazzale Aldo Moro, 5, 00185 Roma RM, Italy

⁴

Department of Biochemistry and Emory Integrated Proteomics Core, Emory University School of Medicine, Atlanta, GA 30322, USA

⁵

Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky, Lexington, KY 40504, USA

⁶

Department of Bioengineering, University of California, Berkeley, CA 94720, USA

⁷

Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

⁸

GlaxoSmithKline, Research and Development, King of Prussia, PA 19406, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2021, 22(3), 1186; https://doi.org/10.3390/ijms22031186

Submission received: 16 December 2020 / Revised: 11 January 2021 / Accepted: 13 January 2021 / Published: 26 January 2021

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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Abstract

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.

Keywords: tau; GSK2606414; kinases; MEMRI; TMT proteomics

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MDPI and ACS Style

Koren, S.A.; Hamm, M.J.; Cloyd, R.; Fontaine, S.N.; Chishti, E.; Lanzillotta, C.; Rodriguez-Rivera, J.; Ingram, A.; Bell, M.; Galvis-Escobar, S.M.; et al. Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy. Int. J. Mol. Sci. 2021, 22, 1186. https://doi.org/10.3390/ijms22031186

AMA Style

Koren SA, Hamm MJ, Cloyd R, Fontaine SN, Chishti E, Lanzillotta C, Rodriguez-Rivera J, Ingram A, Bell M, Galvis-Escobar SM, et al. Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy. International Journal of Molecular Sciences. 2021; 22(3):1186. https://doi.org/10.3390/ijms22031186

Chicago/Turabian Style

Koren, Shon A., Matthew J. Hamm, Ryan Cloyd, Sarah N. Fontaine, Emad Chishti, Chiara Lanzillotta, Jennifer Rodriguez-Rivera, Alexandria Ingram, Michelle Bell, Sara M. Galvis-Escobar, and et al. 2021. "Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy" International Journal of Molecular Sciences 22, no. 3: 1186. https://doi.org/10.3390/ijms22031186

APA Style

Koren, S. A., Hamm, M. J., Cloyd, R., Fontaine, S. N., Chishti, E., Lanzillotta, C., Rodriguez-Rivera, J., Ingram, A., Bell, M., Galvis-Escobar, S. M., Zulia, N., Di Domenico, F., Duong, D., Seyfried, N. T., Powell, D., Vandsburger, M., Frolinger, T., Hartz, A. M. S., Koren, J., III, ... Abisambra, J. F. (2021). Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy. International Journal of Molecular Sciences, 22(3), 1186. https://doi.org/10.3390/ijms22031186

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Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

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