Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain

The human apolipoprotein E4 (ApoE4) isoform is associated with genetic risk for Alzheimer's disease. To assess the effects of different ApoE isoforms on amyloid plaque formation, human ApoE3 and ApoE4 were expressed in the br ains of transgenic mice under the control of the human transferrin promoter . Mice were crossed with transgenic mice expressing human amyloid precursor protein containing the Swedish mutation (APPsw), which facilitates amyloid beta peptide (A beta) production. The following progeny were selected for characterization: APPsw(+/-) x ApoE3(+/-) and APPsw(+/-), APPsw(+/-) x ApoE 4(+/-) and APPsw(+/-) littermates. All mice analyzed were wild type for the endogenous mouse APP and ApoE genes. Mice expressing ApoE4 in combination with APPsw have accelerated A beta deposition in the brain as assessed ;by enzyme immunoassay for A beta (40) and A beta (42) extractable in 70% formi c acid, by assessment of amyloid plaque formation using thioflavin-S staini ng, and by immunohistochemical staining with antibodies specific for A beta (40) or A beta (42) and the 4G8 monoclonal or 162 polyclonal antibody. No difference in the rate of A beta deposition in the brain was seen in mice e xpressing ApoE3 in combination with APPsw. Thus, our data are consistent wi th the observation in Alzheimer's disease that ApoE4 is associated with inc reased accumulation of A beta in the brain relative to ApoE3.