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

• Published in: Brain research. Molecular brain research. Vol. 109; no. 1; pp. 45 - 55
• Main Authors: Pei, Jin-Jing, Braak, Heiko, An, Wen-Lin, Winblad, Bengt, Cowburn, Richard F, Iqbal, Khalid, Grundke-Iqbal, Inge
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30.12.2002; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer’s disease; Animals; Biological and medical sciences; Brain - anatomy & histology; Brain - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; ERK; Female; Fluorescent Dyes - metabolism; Humans; Immunohistochemistry; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Medical sciences; MEK; Middle Aged; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - metabolism; Neurofibrillary tangles; Neurofibrils - metabolism; Neurology; Neurons - cytology; Neurons - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; tau Proteins - metabolism; Up-Regulation - physiology; MEK; Neurofibrillary tangles; Development and regeneration; Alzheimer’s disease; ERK; Human; Nervous system diseases; Enzyme; Alzheimer disease; Central nervous system disease; Mitogen-activated protein kinase; Degenerative disease; Degeneration; Neurofibrillary tangle; Cerebral disorder
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(02)00488-6

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 β-amyloid in AD.