Aberrant phosphoinositide metabolism in Alzheimer's disease.
Since phosphoinositide-specific phospholipase C (PLC) is one of the key molecules in signal transduction, its involvement was assessed in Alzheimer's disease (AD). The phosphatidyl-inositol (PI)-specific PLC activity in the Alzheimer cytosolic and particulate fractions was not significantly different from that in the control fractions. The PI-specific PLC activity as a function of the free Ca2+ concentration was also similar between control and Alzheimer brains. These results suggest that the PI-specific PLC activity is not altered in AD. Immunostaining of a specific antibody against the PLC isozyme, PLC-delta, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains. Western blot analysis confirmed that PLC-delta was concentrated in the paired helical filament (PHF)-rich fraction of AD brains. PLC-delta marked the same neurons containing tau immunoreactivity and yet tau and PLC-delta often marked different structures within the same neuron, with tau more clearly on NFT and PLC-delta covering it superficially. The double stain with PLC-delta and basic fibroblast growth factor (bFGF) binding suggest that PLC-delta is an intracellular marker, showing little overlap with bFGF binding, an extracellular marker. All of this was consistent with the electron microscopy, with PLC-delta being NFT associated. Antibodies to other PLC isozymes did not produce positive immunostaining of these pathologic structures. Moreover, diffuse and amorphous deposits of PLC-delta were found to precede the accumulation of fibrillary deposits. These results suggest that PLC-delta accumulation plays a possible role in the formation of intraneuronal inclusions in AD.
Shimohama
S
S
Department of Neurology, Faculty of Medicine, Kyoto University, Japan.
Fujimoto
S
S
Tresser
N
N
Richey
P
P
Perry
G
G
Whitehouse
P J
PJ
Homma
Y
Y
Takenawa
T
T
Taniguchi
T
T
Suenaga
T
T
D000544:Alzheimer Disease / Q000201:enzymology*; D001921:Brain / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010716:Phosphatidylinositols / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism*
D007527:Isoenzymes; D010716:Phosphatidylinositols; D010727:Phosphoric Diester Hydrolases; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase