ABSTRACT
Intraneuronal accumulation of ß-amyloid (Aß)42 is one of the earliest pathological events in humans and in animal models of Alzheimer's disease (AD). Apolipoprotein E 4 (APOE4) is the major identified genetic risk factor for late-onset AD, with Aß deposition beginning earlier in apoE4-positive subjects. To directly determine the effects of APOE genotype on intraneuronal accumulation of Aß1-42 at the onset of AD pathogenesis, we introduced lentiviral Aß1-42 into the cortex of APOE targeted replacement (TR) mice at the age of 8-9 months. We demonstrated a significant isoform-dependent effect of human APOE, with dramatically enhanced intracellular Aß1-42 deposits in the cerebral cortex of APOE4-TR mice 2 weeks after injection. Double-immunofluorescent staining showed that intracellular accumulation of lentiviral Aß1-42 was mainly present in neurons, localized to late endosomes/lysosomes. This intraneuronal accumulation of Aß1-42 correlated with increased tau phosphorylation and cell death in the ipsilateral cortex around the injection site. Aß1-42 was also observed in microglia, but not in astrocytes. Quantitative analysis revealed more neurons with Aß1-42 while less microglia with Aß1-42 nearest to the injection site of Aß1-42 lentivirus in APOE4-TR mice. Finally, apoE was present in neurons of the ipsilateral cortex of APOE-TR mice at 2 weeks after lentivirus injection, in addition to astrocytes and microglia in both the ipsilateral and contralateral cerebral cortex. Taken together, these results demonstrate that apoE4 tips the balance of the glial and neuronal Aß toward the intraneuronal accumulation of Aß.
