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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Weisgraber, Karl H. Huang, Yadong Giedt, Gretchen Ye, Shiming Müllendorff, Karin Cohen, Fred E. Kuntz, Irwin D. Meng, Elaine C. Mahley, Robert W. Dong, Liming |
| Description | Author Affiliation: Ye S ( Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA.); |
| Abstract | 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 (Abeta) peptides. We examined the effects of apoE isoforms on the processing of amyloid precursor protein (APP) and on Abeta production in rat neuroblastoma B103 cells stably transfected with human wild-type APP695 (B103-APP). Lipid-poor apoE4 increased Abeta 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 Abeta 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 Abeta 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 51 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Amyloid Beta-Peptides Metabolism Apolipoproteins E Chemistry Neurons Cytology Biosynthesis Animals Apolipoprotein E3 Apolipoprotein E4 Genetics Secretion Cell Line, Tumor Cholesterol LDL-Receptor Related Proteins Models, Molecular Protein Isoforms Protein Processing, Post-Translational Protein Structure, Tertiary Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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