An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice

Sylvie Le Corre; Hans W. Klafki; Nikolaus Plesnila; Gabriele Hübinger; Axel Obermeier; Heidi Sahagún; Barbara Monse; Pierfausto Seneci; Jada Lewis; Jason Eriksen; Cynthia Zehr; Mei Yue; Eileen McGowan; Dennis W. Dickson; Michael Hutton; Hanno M. Roder

doi:10.1073/pnas.0602913103

An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice

Sylvie Le Corre, Hans W. Klafki, Nikolaus Plesnila, Gabriele Hübinger, Axel Obermeier, Heidi Sahagún, Barbara Monse, Pierfausto Seneci, Jada Lewis, Jason Eriksen, Cynthia Zehr, Mei Yue, Eileen McGowan, Dennis W. Dickson, Michael Hutton, Hanno M. Roder

Neuroscience

Research output: Contribution to journal › Article › peer-review

178 Scopus citations

Abstract

An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.

Original language	English (US)
Pages (from-to)	9673-9678
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	25
DOIs	https://doi.org/10.1073/pnas.0602913103
State	Published - Jun 20 2006

Keywords

Alzheimer's disease
Extracellular signal-regulated kinase inhibitor
Paired helical filament
Tangles

ASJC Scopus subject areas

General

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10.1073/pnas.0602913103

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Le Corre, S., Klafki, H. W., Plesnila, N., Hübinger, G., Obermeier, A., Sahagún, H., Monse, B., Seneci, P., Lewis, J., Eriksen, J., Zehr, C., Yue, M., McGowan, E., Dickson, D. W., Hutton, M., & Roder, H. M. (2006). An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. Proceedings of the National Academy of Sciences of the United States of America, 103(25), 9673-9678. https://doi.org/10.1073/pnas.0602913103

Le Corre, S, Klafki, HW, Plesnila, N, Hübinger, G, Obermeier, A, Sahagún, H, Monse, B, Seneci, P, Lewis, J, Eriksen, J, Zehr, C, Yue, M, McGowan, E, Dickson, DW, Hutton, M & Roder, HM 2006, 'An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 25, pp. 9673-9678. https://doi.org/10.1073/pnas.0602913103

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abstract = "An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.",

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AU - Obermeier, Axel

AU - Sahagún, Heidi

AU - Monse, Barbara

AU - Seneci, Pierfausto

AU - Lewis, Jada

AU - Eriksen, Jason

AU - Zehr, Cynthia

AU - Yue, Mei

AU - McGowan, Eileen

AU - Dickson, Dennis W.

AU - Hutton, Michael

AU - Roder, Hanno M.

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AB - An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.

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An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice

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