Analysis of the mechanisms of beta-amyloid accumulation by 68kDa serine protease with beta-secretase activity
| Project/Area Number |
07670173
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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 |
Pathological medical chemistry
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| Research Institution | KOBE UNIVERSITY |
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Principal Investigator |
MATSUMOTO Akira KOBE UNIVERSITY,SCHOOL OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 助教授 (80181759)
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| Co-Investigator(Kenkyū-buntansha) |
BABA Hisamitsu KOBE UNIVERSITY,SCHOOL OF MEDICINE,RESEARCH ASSOCIATE, 医学部, 助手 (70189728)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | beta-amyloid / serine protease / aggregation / Alzheimer's disease / proteolysis / cDNA / heparan sulfate / extracellular matrix / 脳老化 / 分子生物学 / βセクレターゼ / 細胞外マトリックス / 陰性荷電 / ヘパラン硫酸 / 複合糖質 |
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| Research Abstract |
(1) Establishment of the efficient preparation method for the 68kDa serine protease and its related enzymes utilizing antibody-specific and ligand-specific affinity chromatography.
(2) Establishment of an in vitro system mimicking human brain extracellular matrix to analyze functions of these proteases.
(3) Analysis of aggregation and degradation of natural Abeta-harboring substrates. Highmolecular weight aggregated product was most efficiently generated when C-terminal substrates were co-incubated with collagen type 4. On the other hand, N-terminal substrates with extracellular domains of APP were excellent substrates for this protease, and it seems that the efficiency of proteolysis is related to the glycoconjugate binding do main within beta-amyloid.
(4) Analysis using sugar-modifying enzymes revealed that human brain 68kDa serine protease contains heparan sulfate giycoconjugates. This finding implies that both substrate and protease are modified by glycoconjugates, suggesting their significance in specificity and topological restriction of proteolysis in vivo.
(5) Structural analysis of cDNA encoding the protease.
(6) Future prospects : Several proteases with similar biochemical properties were prepared from human brain by antibody-specific and ligand-specific affinity chromatography. Further study of these enzymes seems to be important in view of a series of serine proteases participating in blood coagulation. Isolation and identification of specific inhibitors are also of interest to understand the functions of these proteases.
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Report
(3 results)
Research Products
(21 results)
