Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S
| Autor: | Dennis J. Selkoe, J. S. Munger, Cynthia A. Lemere, W. S. F. Wong, David B. Teplow, Christian Haass, Guo-Ping Shi, Harold A. Chapman |
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| Jazyk: | angličtina |
| Rok vydání: | 1995 |
| Předmět: |
Cathepsin L
Molecular Sequence Data Gene Expression Cathepsin E Biology Kidney Transfection Biochemistry Cathepsin A Cathepsin D Cathepsin B Cathepsin C Cell Line Amyloid beta-Protein Precursor Cathepsin O Cathepsin H Alzheimer Disease Endopeptidases Humans Amino Acid Sequence Molecular Biology Cathepsin S Neurons Amyloid beta-Peptides Brain Cell Biology Molecular biology Cathepsins Immunohistochemistry Cysteine Endopeptidases biology.protein Lysosomes Neuroglia Research Article |
| Popis: | To investigate the potential contribution of the lysosomal compartment in the processing of amyloid precursor protein (APP) to amyloid beta-peptides (A beta s), we stably overexpressed a series of lysosomal proteases (the cysteine proteases, cathepsins B, L and S, and the aspartic protease, cathepsin D) in a human kidney epithelial cell line (293) transfected to express high levels of beta APP. Preliminary experiments indicated that 293 cells endogenously synthesize cathepsins B, L and D, but not cathepsin S. A beta secretion was assessed by immunoprecipitation and ELISA and found to be increased approximately 2-fold following cathepsin S expression, but to be unchanged (cathepsins B, L) or decreased (cathepsin D) in the other double transfectants. E-64d, an inhibitor of lysosomal cysteine proteases, significantly reduced A beta secretion by the cathepsin S transfectants, but had no effect on cells expressing the other proteases. Radiosequencing of A beta secreted by cathepsin S-expressing cells revealed that a previously unreported variant beginning at Met -1 (relative to the most common A beta N-terminus, Asp -1) accounted for most of the increase in A beta secretion. Immunostaining of human brain sections revealed cathepsin S in cortical neurons and glia in samples of brain from patients with Alzheimer's disease. These results provide evidence in living cells for a pathway in which cathepsin S generates A beta from amyloidogenic fragments of beta APP in the endosomal/lysosomal compartment. This pathway appears to be inducible, distinct from a constitutive pathway used by 293 and other cells to generate A beta, and may be relevant to the pathogenesis of Alzheimer's disease. |
| Databáze: | OpenAIRE |
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