| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Outline of Final Research Achievements |
γ-secretase generates amyloid β peptide (Aβ) from amyloid precursor protein (APP) through multi step cleavage, such as endoproteolysis and trimming. In the study, we reconstituted human γ-secretase complex and APP in yeast and identified activating mutations in the catalytic subunit of γ-secretase presenilin 1 (PS1), and the regulatory subunit Aph1aL. We introduced these mutants in yeast and mammalian cells and found that the mutations increase the stepwise cleavage activity (cleavage and trimming), and in particular, decrease long-chain Aβ42 by raising trimming. We also clarified the conformational changes of each subunit with activation. It has become an important finding in the development of antidementia drugs that reduce the production of highly toxic Aβ42 involved in the onset of dementia.
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