Cited by 247Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease

Pei, Jin-Jing, Braak, Heiko, An, Wen-Lin, Winblad, Bengt, Cowburn, Richard F, Iqbal, Khalid, Grundke-Iqbal, Inge·2002·Molecular Brain Research

DOI 10.1016/s0169-328x(02)00488-6

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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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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
ORCID: Braak, Heiko
Winblad, Bengt
Iqbal, Khalid
Venue: Molecular Brain Research
Publisher: Elsevier BV
Published: 2002-12
Volume: 109
Issue: 1-2
Pages: 45-55
ISSN: 0169-328X (ISSN-L)
DOI: 10.1016/s0169-328x(02)00488-6
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease

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