Phosphorylated map kinase (ERK1, ERK2) expression is associated with earlytau deposition in neurones and glial cells, but not with increased nuclearDNA vulnerability and cell death, in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration

Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in taupathies. The present study examines the inv olvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer dis ease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and c orticobasal degeneration (CBD), by Western blotting, single and double-labe lling immunohistochemistry, and p21Ras activation assay. Since this pathway is also activated in several paradigms of cell death and cell survival, ac tivated ERK expression is also analysed with double-labelling immunohistoch emistry and in situ end-labelling of nuclear DMA fragmentation to visualise activated ERK in cells with increased nuclear DNA vulnerability. The MEK1 antibody recognises one band of 45 kD that identifies phosphorylation-indep endent MEK1, whose expression levels are not modified in diseased brains. T he ERK antibody recognises one band of 42 kD corresponding to the molecular weight of phosphorylation-independent ERK2; the expression levels, as well as the immunoreactivity of ERK in individual cells, is not changed in AD, PID, PSP and CBD. The antibody MAPK-P distinguishes two bands of 44 kD and 42 kD that detect phosphorylated ERK1 and ERK2. MAPK-P expression levels, a s seen with Western blotting, are markedly increased in AD, PID, PSP and CB D. Moreover, immunohistochemistry discloses granular precipitates in the cy toplasm of neurones in AD, mainly in a subpopulation of neurones exhibiting early tau deposition, whereas neurones with developed neurofibrillary tang les are less commonly immunostained. MAPK-P also decorates neurones with Pi ck bodies in PID, early tau deposition in neurones in PSP and CBD, and cort ical achromatic neurones in CBD. In addition, strong MAPK-P immunoreactivit y is found in large numbers of tau-positive glial cells in PSP and CBD, as seen with double-labelling immunohistochemistry. Yet no co-localisation of enhanced phosphorylated ERK immunoreactivity and nuclear DNA fragmentation is found in AD, PID, PSP and CBD. Finally, activated Pas expression levels are increased in AD cases when compared with controls. These results demons trate increased phosphorylated (active) ERK expression in association with early tau deposition in neurones and glial cells in taupathies, and suggest activated Ras as the upstream activator of the MEK/ERK pathway of tau phos phorylation in AD.