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.
Shimohama
S
S
Department of Neurology, Faculty of Medicine, Kyoto University, Japan.
Matsushima
H
H
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