Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

• Type of Material: Article
• Authors: Shon A. Koren, University of Florida; Matthew J. Hamm, University of Florida; Ryan Cloyd, University of Kentucky; Sarah N. Fontaine, University of Kentucky; Emad Chishti, University of Kentucky; Chiara Lanzillotta, Sapienza University Rome; Jennifer Rodriguez-Rivera, University of Kentucky; Alexandria Ingram, University of Kentucky; Michelle Bell, University of Kentucky; Sara M. Galvis-Escobar, University of Florida; Nicholas Zulia, University of Florida; Fabio Di Domenico, Sapienza University Rome; Duc Duong, Emory University; Nicholas Seyfried, Emory University; David Powell, University of Kentucky; Moriel Vandsburger, University of California Berkeley; Tal Frolinger, Icahn School of Medicine at Mount Sinai; AMS Hartz, University of Kentucky; John Koren, University of Florida; Jeffrey M. Axten, GlaxoSmithKline; Nicholas J. Laping, GlaxoSmithKline; Jose F. Abisambra, University of Florida
• Language: English
• Date: 2021-02-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms22031186
• Title of Journal or Parent Work: International Journal of Molecular Sciences
• Volume: 22
• Issue: 3
• Start Page: 1
• End Page: 17
• Grant/Funding Information: This work was supported by the Alzheimer’s Association NIRG-14-322441, Department of Defense AZ140097, NIH/NIMHD L32 MD009205-01, NIH 1R21NS093440, NIH/NINDS 1R01 NS091329-01.
• Keywords: Chemistry, Multidisciplinary; Brain; Life Sciences & Biomedicine; GSK2606414; Chemistry; TMT proteomics; Physical Sciences; tau; Science & Technology; MEMRI; kinases; Biochemistry & Molecular Biology
• Research Categories: Biology, Neuroscience; Biology, Physiology; Biology, Molecular; Chemistry, Biochemistry

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.