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

Research output: Contribution to journalArticle

168 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)9673-9678
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number25
DOIs
StatePublished - Jun 20 2006

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Neurofibrillary Tangles
Transgenic Mice
Tauopathies
Blood-Brain Barrier
Neurodegenerative Diseases
Phosphotransferases
Pathology
staurosporine aglycone

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. / Le Corre, Sylvie; Klafki, Hans W.; Plesnila, Nikolaus; Hübinger, Gabriele; Obermeier, Axel; Sahagún, Heidi; Monse, Barbara; Seneci, Pierfausto; Lewis, Jada; Eriksen, Jason; Zehr, Cynthia; Yue, Mei; McGowan, Eileen; Dickson, Dennis W; Hutton, Michael; Roder, Hanno M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 25, 20.06.2006, p. 9673-9678.

Research output: Contribution to journalArticle

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
Le Corre, Sylvie ; Klafki, Hans W. ; Plesnila, Nikolaus ; Hübinger, Gabriele ; Obermeier, Axel ; Sahagún, Heidi ; Monse, Barbara ; Seneci, Pierfausto ; Lewis, Jada ; Eriksen, Jason ; Zehr, Cynthia ; Yue, Mei ; McGowan, Eileen ; Dickson, Dennis W ; Hutton, Michael ; Roder, Hanno M. / An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 25. pp. 9673-9678.
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