Elevated Aβ and Apolipoprotein E in AβPP Transgenic Mice and Its Relationship to Amyloid Accumulation in Alzheimer’s Disease

Background: Amyloid-β (Aβ) accumulates in plaques and as cerebral amyloid angiopathy (CAA) in the brains of both Alzheimer’s disease (AD) patients and transgenic AβPPswe/tg2576 (tg2576) mice. Increasingly, evidence in humans and mice shows this process to be modulated by apolipoprotein E (apoE). Materia fls and Methods: To explore this relationship, we measured apoE and Aβ levels in brains of tg2576 mice and controls at intervals between 2 and 20 months. In addition, Aβ concentrations in plasma and muscle of these animals were also quantified. Results: Quite strikingly, we found that the amount of tg2576 mice brain apoE was elevated by an average of 45%, relative to the control mice from 2 months on. The level of brain apoE soared after 14 months to almost 60% greater than the level found in control mice. Aβ concentrations in brains before 9 months were less than 2 ng/mg of protein, but by 14 months concentrations rose to 8.7 ng/mg, and by 20 months to 47 ng/mg. In plasma, we noted that the levels of Aβ in tg2576 mice declined from above 30 ng/ml prior to 12 months to 14 ng/ml by 14 months. Histology showed that Aβ plaques and CAA began to be discernible in the tg2576 mice at about 9 and 20 months of age, respectively. Conclusions: ApoE was immunocytochemically detected in neuritic plaques that were positive for thioflavine-S. We suggest that the elevation of brain apoE in tg2576 mice participates in an age-related dys-regulation of Aβ clearance and signals the start of Aβ sequestration during the time of cognitive dysfunction.