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

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 2

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Human apo E4 expression by astrocytes suppresses Aβ deposition, as asses...
Human apo E4 expression by astrocytes suppresses Aβ deposition, as assessed by anti-Aβ immunostaining in APPV717F+/– mice at 39 weeks of age. APPV717F+/–, mouse apo E+/+ animals had numerous hippocampal and some cortical Aβ-IR deposits by 39 weeks of age (a and b). APPV717F+/–, apo E–/– animals had less Aβ-IR deposits than those expressing mouse apo E; however, there was still a significant amount of deposition in all animals assessed. In addition, the hippocampal Aβ that was present in apo E–/– mice was in a different distribution, with more Aβ immunoreactivity in the hilus of the dentate gyrus and none in the cortex (c and d). In APPV717F+/–, apo E4+/– line 22 animals, hippocampal Aβ immunoreactivity was completely absent in most animals (e and f). Scale bar: 60 μm for b, d, and f; 150 μm for a, c, and e. Aβ, amyloid β; APP, amyloid precursor protein; IR, immunoreactive.