期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 51, 页码 18700-18705出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508693102
关键词
Alzheimer's disease; neurodegeneration
资金
- NHLBI NIH HHS [R01 HL037063, R01 HL064162, HL37063, HL64162] Funding Source: Medline
- NIA NIH HHS [AG22074, P01 AG022074] Funding Source: Medline
- NINDS NIH HHS [R21 NS046465, NS46465] Funding Source: Medline
Apolipoprotein (apo) E4 is a major risk factor for Alzheimer's disease, and many studies have suggested that apoE has isoform-specific effects on the deposition or clearance of amyloid beta (A beta) peptides. We examined the effects of apoE isoforms on the processing of amyloid precursor protein (APP) and on A beta production in rat neuroblastoma B103 cells stably transfected with human wild-type APP695 (B103-APP). Lipid-poor apoE4 increased A beta production in B103-APP cells to a greater extent than lipid-poor apoE3 (60% vs. 30%) due to more pronounced stimulation of APP recycling by apoE4 than apoE3. The difference in A beta production was abolished by preincubating the cells with the receptor-associated protein (25 nM), which blocks the low-density lipoprotein receptor-related protein (LRP) pathway, or by reducing LRP expression by small interference RNA. The differences were also attenuated by replacing Arg-61 with threonine in apoE4 or pretreating apoE4 with small molecules, both of which abolish apoE4 intramolecular domain interaction. Thus, apoE4 appears to modulate APP processing and A beta production through both the LRP pathway and domain interaction. These findings provide insights into why apoE4 is associated with increased risk for Alzheimer's disease and may represent a potential target for drug development.
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