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Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target

  • Author(s): Ye, S M
  • Huang, Y D
  • Mullendorff, K
  • Dong, L M
  • Giedt, G
  • Meng, E C
  • Cohen, F E
  • Kuntz, I D
  • Weisgraber, Karl H
  • Mahley, R W
  • et al.
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 (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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