DEVELOPMENT OF NOVEL β-AMYLOID GENERATION SYSTEM AND ITS APPLIMENT FOR DRUG SCREENING

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In Alzheimer's disease (AD), the β-amyloid peptide (Aβ) is thought to be produced as a results of the aberrant metabolism of APP. APP cytoplasmic domain contains a novel and important signal for APP metabolism. A single amino acid mutation that changed arginine at amino acid 672 of APP695 to a non-basic amino acid greatly increase the production of intracellular CTFβ, but do not results in increased secretion of Aβ. Further expression of presenilin (PS1) cleaved CTFβ at γ-site and results in great amount of Aβ generation. This cellular system can separate γ-cleavage of CTFβ from prior β-cleaving reaction, and indicated that the APP metabolism differs from normal metabolic pathway in which γ-cleavage occurs just after β-cleavage. Using this cell system, it is possible to screen compounds that suppress Aβ production. We further report that a transcription factor, NF-κB/p65, induces increased secretion of amyloidogenic Aβ42 but not Aβ40. The results suggest that the gene product under the expression control of NF-κB plays an important role in Aβ generation. This may be also a novel target to develop drug which suppresses Aβ generation.