TY - JOUR
T1 - Broad kinase inhibition mitigates early neuronal dysfunction in tauopathy
AU - Koren, Shon A.
AU - Hamm, Matthew J.
AU - Cloyd, Ryan
AU - Fontaine, Sarah N.
AU - Chishti, Emad
AU - Lanzillotta, Chiara
AU - Rodriguez-Rivera, Jennifer
AU - Ingram, Alexandria
AU - Bell, Michelle
AU - Galvis-Escobar, Sara M.
AU - Zulia, Nicholas
AU - Di Domenico, Fabio
AU - Duong, Duc
AU - Seyfried, Nicholas T.
AU - Powell, David
AU - Vandsburger, Moriel
AU - Frolinger, Tal
AU - Hartz, Anika M.S.
AU - Koren, John
AU - Axten, Jeffrey M.
AU - Laping, Nicholas J.
AU - Abisambra, Jose F.
N1 - Publisher Copyright:
© 2021 by the authors.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
KW - GSK2606414
KW - Kinases
KW - MEMRI
KW - TMT proteomics
KW - Tau
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UR - http://www.scopus.com/inward/citedby.url?scp=85099949284&partnerID=8YFLogxK
U2 - 10.3390/ijms22031186
DO - 10.3390/ijms22031186
M3 - Article
C2 - 33530349
AN - SCOPUS:85099949284
SN - 1661-6596
VL - 22
SP - 1
EP - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 3
M1 - 1186
ER -