Study on cholesterol-dependent regulatory mechanisms of amyloid precursor protein processing in membrane microdomains
| Project/Area Number |
18500283
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Juntendo University |
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Principal Investigator |
SAKURAI Takashi Juntendo University, School of Medicine, Professor (70225845)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,110,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | amvloid / Alzheimer's disease / microdomains / 膜ラフト |
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| Research Abstract |
Cholesterol-dependent cleavage of amyloid precursor protein (APP) by beta-secretase (BACE1) in lipid rafts is thought to be a critical regulatory event in generating amyloid-beta peptide, which plays a key role in the pathogenesis of Alzheimer's disease. To investigate the underlying molecular mechanisms of this process in neurons, we analyzed immunoisolated, APP-containing, detergent-resistant membranes from mouse and rat brains. APP was incorporated into cholesterol-dependent lipid-protein complexes linked through a network of protein interactions, which largely excluded BACE1. In copatching experiments, APP was preferentially associated with microdomains marked by GPI-anchored prion protein and not BACE 1-containing microdomains. Protein interactions were necessary for association with the prion-containing microdomains and mediated inhibitory effects on APP-BACE1 interaction and beta-cleavage. Thus we propose a novel regulatory mechanism of APP processing through differential association with distinct microdomains controlled by protein interactions.
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