The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease
Abstract
The abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) has been proposed to involve the extracellular-signal-regulated protein kinase (ERK) of the mitogen-activated protein (MAP) kinase family. ERK is phosphorylated and thereby activated by MAP kinase kinase (MEK). In the present study, we determined the intracellular and regional distribution of the active forms of both MEK1/2 and ERK1/2, i.e. p-MEK1/2 and p-ERK1/2 in the entorhinal, hippocampal, and temporal cortices of 49 brains staged for neurofibrillary changes according to Braak and Braak's protocol. We found that p-MEK1/2 and p-ERK1/2 were present in the initial stages of neurofibrillary degeneration in the projecting neurons in the transentorhinal region, and extended into other brain regions co-incident with the progressive sequence of neurofibrillary changes up to and including Braak stage VI. It appeared that the accumulation of p-MEK1/2 and p-ERK1/2 was initiated in the cytoplasm of pretangle neurons in varying size granules, which grew into large aggregates co-existing with the progressive development of neurofibrillary tangles. Accumulation of p-MEK1/2 and p-ERK1/2 was found in cases with stages I-III neurofibrillary degeneration, which were devoid of amyloid deposition. These data provide direct in situ evidence consistent with the possible involvement of MAP kinase pathway in the hyperphosphorylation of tau and the presence of this lesion before deposition of beta-amyloid in AD.
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“ERK can phosphorylate tau (29), and elevated activity of MAPK/ERK has been reported in several tauopathies and may play a role in early stages of neurofibriliary tangle (NFT) formation (82,130,131).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [130]
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Moloney, A. M., Griffin, R. J., Timmons, S., O’Connor, R., Ravid, R., & O’Neill, C. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.04.002 · Cited by 764
Tau protein kinases: Involvement in Alzheimer's disease
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Metadata
- Authors
- Pei, J.-J., Braak, H., An, W.-L., Winblad, B., Cowburn, R. F., Iqbal, K., & Grundke-Iqbal, I.
- Affiliations
- Karolinska Institutet (SE)
- Goethe University Frankfurt (DE)
- Corresponding author
- Pei, Jin-Jing
- Venue
- Molecular Brain Research
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 109
- Issue
- 1-2
- Pages
- 45-55
- ISSN
- 0169-328X (ISSN-L)
- OpenAlex
- W2046431926
- Cited by
- 247
- References
- 62
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 6 · 2023: 8 · 2022: 19 · 2021: 12 · 2020: 12 · 2019: 12 · 2018: 12 · 2017: 11 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 7 · 2012: 11
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag008076-09, 5r01ns018105-17)
- National Institute on Aging (AG19158, AG 08076, R01AG019158)
- National Institute of Neurological Disorders and Stroke (NS 18105)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neurofibrillary degeneration, tau hyperphosphorylation, ERK1/2, MEK1/2, MAPK signaling, neurofibrillary tangles, Braak staging, entorhinal cortex, hippocampus, temporal cortex, amyloid deposition
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Animals, Brain, Female, Fluorescent Dyes, Humans, Immunohistochemistry, Male, Middle Aged, Neurofibrils, Neurons, Phosphorylation, Protein-Tyrosine Kinases, Up-Regulation, tau Proteins, Protein Serine-Threonine Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinase 3, MAP Kinase Kinase 1, MAP Kinase Kinase 2
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