期刊
NEUROBIOLOGY OF DISEASE
卷 42, 期 3, 页码 221-230出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2011.01.005
关键词
Beta-amyloid; Alzheimer's disease; Scavenger receptors; Lysosomal degradation
资金
- NSC [94-2321-B-010-006, NSC99-2320-B-010-012]
- Brain Research Center [99ACB6-2]
- Ministry of Education-Aim for the Top University [98A-C-D105]
- Mackey memorial hospital [MMH-YM-9903]
The accumulation of soluble oligomeric amyloid-beta peptide (oA beta) proceeds the formation of senile plaques and contributes to synaptic and memory deficits in Alzheimer's disease (AD). The mechanism of mediating microglial oA beta clearance remains unclear and thought to occur via scavenger receptors (SRs) in microglia. SRs respond to their ligands in a subtype-specific manner. Therefore, we sought to identify the specific subtypes of SRs that mediate oA beta internalization and proteases that degrade oA beta species in naive primary microglia. The component of oA beta species were characterized by western blot analysis, analytical ultracentrifugation analysis, and atomic force microscopy. The oA beta species remained soluble in the medium and microglial lysates during incubation at 37 degrees C. SR-A, but not CD36, mediated oA beta internalization in microglia as suggested by the use of subtype-specific neutralizing antibodies and small interfering RNAs (siRNAs). Immunoprecipitation analysis showed that oA beta interacted with SR-A on the plasma membrane. After internalization, over 40% of oA beta vesicles were trafficked toward lysosomes and degraded by cysteine proteases, including cathepsin B. The inhibitors of proteasome, neprilysin, matrix metalloproteinases, and insulin degrading enzyme failed to protect internalized oA beta from degradation. Our study suggests that SR-A and lysosomal cathepsin B are critical in microglial oA beta clearance, providing insight into how microglia are involved in the clearance of oA beta and their roles in the early stages of AD. (c) 2011 Elsevier Inc. All rights reserved.
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