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Secretion of beta-amyloid precursor protein involves multiple cleavage sites
Z Zhong1, J Higaki, K Murakami
1Scios Nova Inc., Mountain View, California 94043.
The Journal of Biological Chemistry
|January 7, 1994
Summary
Alzheimer's disease involves beta-amyloid precursor protein (beta-APP) cleavage. This study identifies multiple cleavage sites for beta-APP secretion, varying by cell type, suggesting complex proteolytic processing in Alzheimer's disease pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by beta-amyloid peptide deposits.
- Beta-amyloid precursor protein (beta-APP) is proteolytically processed to generate beta-amyloid.
- Secretory cleavage of beta-APP releases its amino-terminal portion and a carboxyl-terminal fragment.
Purpose of the Study:
- To characterize the proteolytic cleavage sites involved in beta-APP secretion.
- To investigate variations in cleavage sites across different cellular backgrounds.
Main Methods:
- Amino acid sequence analysis of the 9-kDa carboxyl-terminal fragment of beta-APP.
- Production of recombinant beta-APP using a vaccinia virus expression system in CV-1 cells.
- Analysis of endogenous beta-APP from Down's syndrome fibroblasts.
- Characterization of beta-APP mutants lacking specific amino acids.
Main Results:
- In CV-1 cells, 60% of cleavage occurred after Lys16, and 40% after Phe19.
- In Down's syndrome fibroblasts, cleavage sites were identified after Phe19, Glu22, and Gly25.
- Mutant beta-APP studies revealed cleavage sites after Glu11 and His13 when Lys16 was absent.
Conclusions:
- Beta-APP secretion involves multiple proteinases.
- The specific proteinases involved in beta-APP cleavage can differ between cell types.
- These findings contribute to understanding the complex proteolytic mechanisms in Alzheimer's disease.