Phosphorylated Map Kinase (ERK1, ERK2) Expression is Associated with Early Tau Deposition in Neurones and Glial Cells, but not with Increased Nuclear DNA 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 tau pathies. The present study examines the involvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP)...

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Published in:Brain pathology (Zurich, Switzerland) Switzerland), 2001-04, Vol.11 (2), p.144-158
Main Authors: Ferrer, I., Blanco, R., Carmona, M., Ribera, R., Goutan, E., Puig, B., Rey, M.J., Cardozo, A., Viñals, F., Ribalta, T.
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Basal Ganglia Diseases - metabolism
Basal Ganglia Diseases - pathology
Cell Death
Cell Nucleus - metabolism
Cell Nucleus - pathology
Cerebral Cortex - pathology
DNA - metabolism
DNA Fragmentation
Female
Humans
Male
Middle Aged
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - metabolism
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neuroglia - metabolism
Neuroglia - pathology
Neurons - metabolism
Neurons - pathology
Phosphorylation
Pick Disease of the Brain - metabolism
Pick Disease of the Brain - pathology
Proto-Oncogene Proteins p21(ras) - metabolism
Supranuclear Palsy, Progressive - metabolism
Supranuclear Palsy, Progressive - pathology
tau Proteins - metabolism
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Summary:Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in tau pathies. The present study examines the involvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), by Western blotting, single and double‐labelling immunohistochemistry, and p21Ras activation assay. Since this pathway is also activated in several paradigms of cell death and cell survival, activated ERK expression is also analysed with double‐labelling immunohistochemistry and in situ end‐labelling of nuclear DNA fragmentation to visualise activated ERK in cells with increased nuclear DNA vulnerability. The MEK1 antibody recognises one band of 45 kD that identifies phosphorylation‐independent MEK1, whose expression levels are not modified in diseased brains. The 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, as seen with Western blotting, are markedly increased in AD, PiD, PSP and CBD. Moreover, immunohistochemistry discloses granular precipitates in the cytoplasm of neurones in AD, mainly in a subpopulation of neurones exhibiting early tau deposition, whereas neurones with developed neurofibrillary tangles are less commonly immunostained. MAPK‐P also decorates neurones with Pick bodies in PiD, early tau deposition in neurones in PSP and CBD, and cortical achromatic neurones in CBD. In addition, strong MAPK‐P immunoreactivity 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 Ras expression levels are increased in AD cases when compared with controls. These results demonstrate 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 phosphorylation in AD.
ISSN:1015-6305
1750-3639
DOI:10.1111/j.1750-3639.2001.tb00387.x