期刊
NEUROBIOLOGY OF AGING
卷 29, 期 5, 页码 707-715出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2006.12.001
关键词
Alzheimer's disease; a beta; macrophages; clearance; mass spectrometry
资金
- NIDDK NIH HHS [R01 DK027083, DK27083, R01 DK054317, R37 DK027083-28, DK54317, R01 DK054317-08, R01 DK027083-26, R37 DK027083, R37 DK027083-27, R01 DK054317-07] Funding Source: Medline
- NINDS NIH HHS [R01 NS034761-08, R01 NS034761-06, R01 NS034761-07, R01 NS034761, NS 34761] Funding Source: Medline
Cultured microglia internalize fibrillar amyloid A beta (fA beta) and deliver it to lysosomes. Degradation of fA beta by microglia is incomplete, but macrophages degrade fA beta efficiently. When mannose-6 phosphorylated lysosomal enzymes were added to the culture medium of microglia, degradation of fA beta was increased, and the increased degradation was inhibited by excess mannose-6-phosphate, which competes for binding and endocytic uptake. This suggests that low activity of one or more lysosomal enzymes in the microglia was responsible for the poor degradation of fA beta. To further characterize the degradation of fA beta in late endosomes and lysosomes, we analyzed fA beta-derived intracellular degradation products in macrophages and microglia by mass spectrometry. Fragments with truncations in the first 12 N-terminal residues were observed in extracts from both cell types. We also analyzed material released by the cells. Microglia released mainly intact A beta I-42, whereas macrophages released a variety of N-terminal truncated fragments. These results indicate that initial proteolysis near the N-terminus is similar in both cell types, but microglia are limited in their ability to make further cuts in the fA beta. (c) 2007 Elsevier Inc. All rights reserved.
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