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.

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Published in International Journal of Molecular Sciences, v. 22, issue 3, 1186.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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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. Moreover, this study was funded in part by a contract from GSK.

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Data are available via ProteomeXchange with identifier PXD023562.

The following are available online at https://www.mdpi.com/1422-0067/22/3/1186/s1, Figure S1: Total duration spent in novel arm is partially rescued in tau transgenic mice treated with GSK2606414, Figure S2: Non-PERK UPR proteins do not have altered transcript levels in 5mo tau transgenic mice, Figure S3: GSK2606414 does not alter phospho-peptide abundance of human P301L MAPT. Figure S4: GSK2606414 treatment for up to 36 d does not cause marked weight loss, Table S1. Top kinase targets of GSK2606414 and relevance to tauopathy, Table S2. Significantly enriched reactome pathways identified by proteomics, Table S3. Human to mouse proteomic comparisons, Table S4. Patient demographics of human proteomic samples. These supplementary materials are also available for download as the additional file listed at the end of this record.

ijms-22-01186-s001.pdf (943 kB)
Supplementary materials