Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease

The epsilon 4 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-beta protein (A beta). To assess the effects of human apo E isoforms on A beta 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 (APP(V717F)) transgene that develop age-dependent AD neuropathology. All mice were on a mouse apo E null (-/-) background. By nine months of age, APP(V717F-/-), apo E-/- mice had developed A beta deposition, and, as reported previously, the quantity of A beta deposits was significantly less than that seen in APP(V717F+/-) 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 A beta deposition at nine months of age in APP(V717F-/-) transgenic mice, even when compared with mice lacking apo E. These findings suggest that human apo E isoforms decrease A beta aggregation or increase A beta 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.