抄録
Alzheimer's disease is a slowly progressive neurodegenerative disorder which causes severe dementia. Amyloid-beta peptide (Aβ) deposition in senile plaques is one of the pathological hallmarks in Alzheimer's disease. Aβ peptide is derived from the amyloid precursor protein (APP) by proteolytic processing by beta-secretase which cleaves APP at the N-terminus of Ab, and by gamma-secretase which cleaves at the C-terminus of Aβ. In spite of extensive research, the precise subcellular localization of Ab generation has not been identified yet. Using the recently developed fluorescence resonance energy transfer (FRET) approach and pulse-chase ELISA, we examined the subcellular localization of interactions between APP and beta-secretase. Our data showed a close APP-BACE interaction in early endosomes, and highlight the cell surface as an additional potential site of APP-BACE interaction. Furthermore, we identified a novel interaction between LRP, an endocytic receptor for APP, and beta-secretase, in the early endosomes and on the cell surface. The interaction between LRP and beta-secretase was not detected when cholesterol was depeleted, suggesting that LRP encounters beta-secretase in the lipid raft of the membranes. Taken together, we propose that APP interacts with beta-secretase in the lipid rafts of the cell membrane and in early endosomes, and that LRP may be a scaffold protein which links APP and BACE upon endocytosis. We believe that investigation of the interaction between APP and its secretases helps us understand the mechanisms of Aβ generation and pathogenesis of Alzheimer's disease. [J Physiol Sci. 2006;56 Suppl:S35]
