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P3‐025: Chronic inhibition of the MEK/ERK pathway fails to delay disease progression in a transgenic animal model of tauopathy
Author(s) -
Bose Suchira,
Cavallini Annalisa,
Murray Tracey,
Baschirotto Lisa,
Czilli Dan,
Cella Claire,
Ward Mark,
Hanmer Jenna,
Sims Helen,
Eberle Elizabeth,
Simmons Aaron,
Sossick Sandra,
Cramer Jeff,
Calligaro David,
Mateo Ana,
Bloem Laura,
Nuthall Hugh,
O'Neill Michael,
Davies Peter,
Goedert Michel,
Hutton Michael,
Szekeres Philip
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.1243
Subject(s) - tauopathy , genetically modified mouse , phosphorylation , tau protein , mapk/erk pathway , microbiology and biotechnology , transgene , chemistry , neurite , pathogenesis , neuroscience , neurodegeneration , alzheimer's disease , biology , medicine , biochemistry , disease , in vitro , gene
Background: Neurofibrillary tangles (NFT), one of the hallmarks of Alzheimer’s disease (AD), are composed of paired helical filaments (PHF) of abnormally hyperphosphorylated tau. The accumulation of these proteinaceous aggregates in AD correlates with synaptic loss and severity of dementia. Identifying the kinases involved in the pathological phosphorylation of tau may identify novel targets for AD.Methods:We have used an unbiased approach to study the effect of 352 human kinases on their ability to phosphorylate tau at epitopes associated with early AD. The kinases were overexpressed together with the longest form of human tau in human neuroblastoma cells. Levels of total and phosphorylated tau (epitopes pS202, pT231, pS235 and pS396/404) were measured in cell lysates using AlphaScreen assays. Results: GSK3a, GSK3b and MAPK13 were found to be the most active tau kinases, phosphorylating tau at all 4 epitopes. Pathway analysis of all the ‘hits’ suggests the Ras family of GTPases (MAPK family) to be a key regulator of tau phosphorylation. Pathway analysis on subgroups of kinases reveals several mechanisms involved in regulating tau expression levels by inhibition or activation of translation.Conclusions: The findings identify novel tau kinases and novel pathways that may be relevant for AD and other tauopathies.