ABSTRACT
<p><b>OBJECTIVES</b>To investigate the changes of nuclear factor (NF-)κBp65 and inflammatory chemotactic factors including monocyte chemoattractant protein 1 (MCP-1/CCL-2), macrophage inflammatory protein 1α (MIP-1α/CCL-3), glial fibrillary acidic protein (GFAP) in brains of the patients with Alzheimer's disease (AD) and reveal the correlation of these factors.</p><p><b>METHODS</b>Ten patients with AD and 8 age-matched control subjects were selected in the study. Immunohistochemistry was performed to determine the protein expression of NF-κBp65, MCP-1, MIP-1α and GFAP. Double-immunohistochemistry was used to detect the expression of GFAP and β-amyloid peptide 1-42 (Aβ(1-42)) in the hippocampus, temporal and frontal cortices.</p><p><b>RESULTS</b>As compared to age-matched controls (the numbers of the positively stained neuronal cells: 0.31 ± 0.20, 0.25 ± 0.20 and 0.25 ± 0.20, respectively), the immunoreactivities of NF-κBp65 in the hippocampus and the temporal and frontal cortices (numbers of the positively stained cells: 3.6 ± 1.5, 2.2 ± 1.2 and 2.2 ± 1.2, respectively) were significantly increased in AD brains. The levels of MCP-1 and MIP-1α in the hippocampus, and the temporal and frontal cortices (numbers of the positively stained neuronal cells: 8.0 ± 1.3, 8.8 ± 1.0, 9.3 ± 1.4, respectively;and 8.1 ± 1.5, 12.5 ± 1.1, 6.4 ± 1.1, respectively) with AD were significantly higher than those of controls (the numbers of the positive neuronal cells: 4.5 ± 0.9, 4.5 ± 0.6, 4.0 ± 1.8, respectively; and 5.0 ± 1.9, 6.3 ± 2.2, 3.8 ± 1.5, respectively). An increased number of glial cells stained with GFAP were observed to extensively distribute around the senile plaques in AD brains. There were significant correlations between NF-κBp65 and these inflammatory chemotactic factors in AD brains.</p><p><b>CONCLUSION</b>Correlative expressions of NF and inflammatory chemotactic factors were found in the brains of AD patients, through a mechanism that may involve the inflammatory response induced by Aβ in the processing of AD.</p>
Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Alzheimer Disease , Metabolism , Pathology , Brain , Metabolism , Pathology , Chemokine CCL2 , Metabolism , Chemokine CCL3 , Metabolism , Frontal Lobe , Metabolism , Pathology , Glial Fibrillary Acidic Protein , Metabolism , Hippocampus , Metabolism , Pathology , Immunohistochemistry , Neuroglia , Metabolism , Pathology , Plaque, Amyloid , Metabolism , Pathology , Temporal Lobe , Metabolism , Pathology , Transcription Factor RelA , MetabolismABSTRACT
Tauopathies such as Alzheimer disease (AD) probably involve a type of phosphorylation imbalance causing the accumulation of abnormally hyperphosphorylated tau in neurons and/or glias. Investigation of R406W tau mutation may provide insight into such abnormal tau hyperphosphorylation, since this mutation causes AD-like dementia and tauopathy in humans and because it has the unique ability to reduce tau phosphorylation in vitro and in cultured cells. Here we show that R406W mutation primarily disrupts tau phosphorylation at Ser404, a priming phosphorylation site of glycogen synthase kinase-3beta (GSK-3beta), thereby reducing subsequent GSK-3beta-mediated phosphorylation at the PHF-1 site (mostly Ser396). In contrast, c-jun N-terminal kinase (JNK) as activated in the mitotic phase directly hyperphosphorylates R406W tau at the PHF-1 site. This was confirmed by PHF-1 hyperphosphorylation of R406W tau in mitotic cells, its association with cytoplasmic JNK activation, and its inhibition by a JNK inhibitor, SP600125. These data unveil the unknown mechanisms of physiological tau phosphorylation at the PHF-1 site and suggest that cytoplasmic JNK activation may play an important role in the abnormal tau hyperphosphorylation associated with R406W tau mutation and in AD.
