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P3‐348: Neuron‐specific regulation of beta‐secretase activity by sphingosine kinase
Author(s) -
Takasugi Nobumasa,
Suzuki Kunimichi,
Isshiki Hayato,
Tomita Taisuke,
Iwatsubo Takeshi
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1917
Subject(s) - sphingosine , sphingosine kinase , microbiology and biotechnology , amyloid precursor protein , amyloid precursor protein secretase , secretion , gene knockdown , sphingosine 1 phosphate , kinase , biology , lipid signaling , chemistry , medicine , alzheimer's disease , endocrinology , biochemistry , receptor , gene , disease
investigated by sedimentation analysis. The distribution of both proteins was also analyzed by immunohistochemistry. Finally, we investigated by Western blot and mRNA analysis whether PS1 mutations could affect AChE expression in a transgenic mouse model. The glycosylation pattern and accessibility to the peripheral binding site of AChE in the mutant mice were studied by lectin-binding and fasciculin affinity matrix, respectively. Results: We report co-immunoprecipitation of PS1 and AChE. Binding occurs through PS1 N-terminal fragment independent of the peripheral binding site of AChE. Co-expression patterns of PS1 and AChE in brain sections from controls and subjects with sporadic or familial AD indicated that PS1 and AChE are located in the same intracellular compartments. PS1-A246E pathogenic mutation expressed in transgenic mice, leads to decreased AChE activity and alteration of AChE glycosylation and peripheral binding site, which may reflect a shift in protein conformation and disturbed AChE maturation. In both, the transgenic mice and humans, mutant PS1 impairs co-immunoprecipitation with AChE. Conclusions: The results indicate that PS1 can interact with AChE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships.