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.
Highlights
IntroductionTauopathies, the most common of which is Alzheimer’s disease (AD), are a group of neurological disorders defined by the neuropathological accumulation of tau protein that creativecommons.org/licenses/by/ 4.0/)
We uncover critical biological processes that contribute to neurotoxic processes driving cognitive dysfunction in tauopathies using a broad kinase inhibitor, GSK2606414
We demonstrate the potential to mitigate the negative functional consequences of tauopathy without altering tau hyper-phosphorylation
Summary
Tauopathies, the most common of which is Alzheimer’s disease (AD), are a group of neurological disorders defined by the neuropathological accumulation of tau protein that creativecommons.org/licenses/by/ 4.0/). No cure for tauopathies exists and current treatment strategies are palliative [1,2]. The disease etiology of tauopathies, AD in particular, are almost certainly multifactorial. A promising strategy to mitigate the complex nature of tauopathies, similar to established approaches for other chronic, progressive diseases, encompass multi-target or combinatorial treatments [3,5]. These strategies are limited by requiring a thorough understanding of the cellular perturbations that underly the disease
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