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Aberrant Phosphoinositide Metabolism in Alzheimer's Disease a
Author(s) -
SHIMOHAMA SHUN,
FUJIMOTO SADAKI,
TRESSER NANCY,
RICHEY PEGGY,
PERRY GEORGE,
WHITEHOUSE PETER J.,
HOMMA YOSHIMI,
TAKENAWA TADAOMI,
TANIGUCHI TAKASHI,
SUENAGA TOSHIHIKO,
KIMURA JUN
Publication year - 1993
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1993.tb23025.x
Subject(s) - phospholipase c , immunostaining , senile plaques , western blot , neurofilament , alzheimer's disease , biology , chemistry , microbiology and biotechnology , biochemistry , pathology , signal transduction , immunohistochemistry , immunology , medicine , disease , gene
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 participate fractions was not significantly different from that in the control fractions. The PI‐specific PLC activity as a function of the free Ca 2+ 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‐δ, 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‐δ was concentrated in the paired helical filament (PHF)‐rich fraction of AD brains. PLC‐δ marked the same neurons containing τ immunoreactivity and yet τ and PLC‐δ often marked different structures within the same neuron, with τ more clearly on NFT and PLC‐δ covering it superficially. The double stain with PLC‐δ and basic fibroblast growth factor (bFGF) binding suggest that PLC‐δ is an intracellular marker, showing little overlap with bFGF binding, an extracellular marker. All of this was consistent with the electron microscopy, with PLC‐δ being NFT associated. Antibodies to other PLC isozymes did not produce positive immunostaining of these pathologic structures. Moreover, diffuse and amorphous deposits of PLC‐δ were found to precede the accumulation of fibrillary deposits. These results suggest that PLC‐δ accumulation plays a possible role in the formation of intraneuronal inclusions in AD.