Signal transduction mechanisms in Alzheimer disease.
The present article focuses on our studies on the metabolism of the inositol phospholipids in Alzheimer disease (AD). The phospholipase C (PLC) isozyme, PLC-delta 1, was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque cores, and neuropil threads in AD brains. Anti-PLC-delta 1 antibody marked the same NFT-bearing neurons containing tau immunoreactivity. Electron microscopic immunocytochemistry revealed that antigenic determinants unique to PLC-delta 1 are mainly present intraneuronally on the amorphous granular components of NFT as well as the abnormal filaments. Although the concentration of PLC-delta 1 protein was significantly higher in the cytosolic fraction of AD cortical tissue than in control brains, the specific activity of PLC-delta 1 is decreased in AD brains. The amounts of PLC-beta 1 and -gamma 1 and type beta protein kinase C were significantly reduced in the membranous fraction of the AD temporal cortical tissues compared with controls. The PLC-delta 1 abnormality was also present in nonneuronal tissues as well as the brains of patients with AD. It was revealed that nitric oxide (NO) formation secondary to Ca2+ influx by N-methyl-D-aspartate (NMDA) receptor activation leads to modifications of PLC-delta 1 similar to those seen in AD brains. These results suggest that altered Ca2+ homeostasis, occurring as a consequence of aberrant phosphoinositide metabolism, may be related to key features of AD such as neurofibrillary degeneration, aberrant amyloid deposits, and neuronal death.
Department of Neurology, Faculty of Medicine, Kyoto University, Japan.
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Shimohama
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Matsushima
D000544:Alzheimer Disease / Q000378:metabolism*; D016923:Cell Death; D006801:Humans; D050356:Lipid Metabolism; D016874:Neurofibrillary Tangles; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction
D010716:Phosphatidylinositols; D011493:Protein Kinase C