An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice
Bibliographic
Year of Publication:
2006
Contact PI Name:
Michael Hutton
Primary Reference (PubMED ID):
Funding Source:
Not Reported
Study Goal and Principal Findings:
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. These 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.
Therapeutic Agent
Therapeutic Information:
Therapeutic Notes:
Mitogen-Activated Protein Kinase 1 (MAPK1/ERK2) has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.
Animal Model
Model Information:
Species:
Mouse
Model Type:
Tau
Model Name:
JNPL3(P301L)
Strain/Genetic Background:
Not Reported
Experimental Design
Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Outcomes
Outcome Measured
Outcome Parameters
Motor Function
Balance Beam Test
Flight Reflex
Coat Hanger Test
Histopathology
Neurofibrillary Tau Tangles
Biochemical
phospho-Tau
Soluble Tau
Insoluble Tau
Aggregated Tau