Apolipoprotein ( apo ) E 4 enhances amyloid peptide production in cultured neuronal cells : ApoE structure as a potential therapeutic target

Content Provider	Semantic Scholar
Author	Ye, Shiming Huang, Yadong Müllendorff, Karin Dong, Liming Giedt, Gretchen Meng, Elaine C. Cohen, Fred E. Kuntz, Irwin D. Weisgraber, Karl H. Mahley, Robert W.
Copyright Year	2005
Abstract	Apolipoprotein (apo) E4 is a major risk factor for Alzheimer’s disease, and many studies have suggested that apoE has isoformspecific effects on the deposition or clearance of amyloid (A ) peptides. We examined the effects of apoE isoforms on the processing of amyloid precursor protein (APP) and on A production in rat neuroblastoma B103 cells stably transfected with human wild-type APP695 (B103-APP). Lipid-poor apoE4 increased A 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 production was abolished by preincubating the cells with the receptor-associated protein (25 nM), which blocks the low-density lipoprotein receptorrelated 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 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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Alternate Webpage(s)	http://www.pnas.org/content/102/51/18700.full.pdf
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article