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.

An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice / S. Le Corre, H. W. Klafki, N. Plesnila, G. Hubinger, A. Obermeier, H. Sahagun, B. Monse, P. Seneci, J. Lewis, J. Eriksen, C. Zehr, M. Yue, E. McGowan, D. W. Dickson, M. Hutton, H. M. Roder. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 103:25(2006 Jun 20), pp. 9673-9678.

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

P. Seneci;
2006

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.
Alzheimer's disease; Extracellular signal-regulated kinase inhibitor; Paired helical filament; Tangles
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
Settore BIO/14 - Farmacologia
20-giu-2006
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/145062
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