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Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease
David M. Holtzman, … , Yuling Sun, Steven M. Paul
David M. Holtzman, … , Yuling Sun, Steven M. Paul
Published March 15, 1999
Citation Information: J Clin Invest. 1999;103(6):R15-R21. https://doi.org/10.1172/JCI6179.
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Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease

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Abstract

The ε4 allele of apolipoprotein E (apo E) is associated with an increased risk for developing Alzheimer's disease (AD). This may be due to interactions between apo E and the amyloid-β protein (Aβ). To assess the effects of human apo E isoforms on Aβ deposition in vivo, we bred apo E3 and apo E4 hemizygous (+/–) transgenic mice expressing apo E by astrocytes to mice homozygous (+/+) for a mutant amyloid precursor protein (APPV717F) transgene that develop age-dependent AD neuropathology. All mice were on a mouse apo E null (–/–) background. By nine months of age, APPV717F+/–, apo E–/– mice had developed Aβ deposition, and, as reported previously, the quantity of Aβ deposits was significantly less than that seen in APPV717F+/– mice expressing mouse apo E. In contrast to effects of mouse apo E, similar levels of human apo E3 and apo E4 markedly suppressed early Aβ deposition at nine months of age in APPV717F+/– transgenic mice, even when compared with mice lacking apo E. These findings suggest that human apo E isoforms decrease Aβ aggregation or increase Aβ clearance relative to an environment in which mouse apo E or no apo E is present. The results may have important implications for understanding mechanisms underlying the link between apo E and AD.

Authors

David M. Holtzman, Kelly R. Bales, Shan Wu, Priyanka Bhat, Maia Parsadanian, Anne M. Fagan, Louis K. Chang, Yuling Sun, Steven M. Paul

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Figure 3

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Quantitation of Aβ deposition in APPV717F+/– mice. The total volume of A...
Quantitation of Aβ deposition in APPV717F+/– mice. The total volume of Aβ-IR deposits in the right hippocampus (a) as well as the volume of the right hippocampus itself (b) was determined in each group of APPV717F+/– mice: apo E3+/– line 37 (n = 4), apo E4+/– line 22 (n = 7), apo E–/– (n = 8), and mouse apo E+/+ (n = 8). There was a significantly smaller volume of Aβ-IR deposits (P < 0.05) in the mice expressing human apo E3 compared with mice expressing no apo E or mouse apo E. The volume of the hippocampus was not statistically different between the different groups. Aβ ELISA for total Aβ in the left hippocampus of APPV717F+/– mice that were apo E4+/–, apo E–/–, and mouse apo E+/+ (c) revealed the same pattern of results as was found for Aβ-IR deposits histologically. *P < 0.05 comparing apo E–/– mice with apo E3+/– and apo E4+/– mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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