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.