| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Alzheimer's disease is a slowly progressive neurodegenerative disorder which causes dementia. The mail pathological hallmarks are senile plaques, neurofibrillary tangles and neuronal loss. The senile plaques are made of amyloid-beta peptides (40-42 amino acids), which are generated from the procursor protein (APP).
The pathological mechanism which underlies the dementia is not exactly known yet, however, the deposition of amyloid-beta is one of the earliest event which may cause other pathological conditions. Therefore, it is now under intensive investigation how and in what cellular compartment amyloid-beta is generated
APP is first cleaved by beta-secretase at its extracellular domain, then the stub (C99) is cleaved by gamma-secretase at its intramembrane domain. Interestingly, the intracellular domain (which is now called AICD) generated by gamma-secretase cleavage, may have a potential role as a transcriptional modulator, in the nucleus. Therefore, we planned to analyze a novel trans
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criptional regulation by gamma-secretase-mediated cleavage.
Then its interaction became less magnificent in lysosomal compartment. We further found that APP with mutation of familial Alzheimer's disease had tighter interaction with BACE. detected by FRET.
Further, this interaction had an impact on actual amyloid-beta generation, since amyloid-beta was detected from the conditioned media by ELISA after the cell surface labeling.
Therefore, the interaction between APP and BACE is strong on the cell surface and in the endosomes, which has actual impact on amyloid-beta generation in vitro.
Furthermore, we detected a novel interaction between BACE and LRP, an endocytic receptor for APP. Interestingly, LRP seems to interact with BACE on the cell surface, especially in the lipid rafts, where, BACE is supposed to encounter APP. The cholesterol depletion experiments showed a decrease of the interaction between BACE and LRP, suggesting that LRP may play as a scaffold to connect APP and BACE on the cell surface.
In this research plan, we confirmed that an endocytic pathway is one of the amyloid-beta generation sites and LRP may play as a scaffold to connect them. Less
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