Broad kinase inhibition mitigates early neuronal dysfunction in tauopathy

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article number1186
Pages (from-to)1-17
Number of pages17
JournalInternational Journal of Molecular Sciences
Volume22
Issue number3
DOIs
StatePublished - Feb 1 2021

Bibliographical note

Funding Information:
Funding: 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.

Funding Information:
Conflicts of Interest: GSK manufactured GSK2606414, which was used in this study. Moreover, this study was funded in part by a contract from GSK. Jeffrey M. Axten and Nicholas Laping are employed by GSK.

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.

Publisher Copyright:
© 2021 by the authors.

Keywords

  • GSK2606414
  • Kinases
  • MEMRI
  • TMT proteomics
  • Tau

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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