Elevated A beta and apolipoprotein E in A beta PP transgenic mice and its relationship to amyloid accumulation in Alzheimer's disease

Background: Amyloid-beta (A beta) accumulates in plaques and as cerebral am yloid angiopathy (CAA) in the brains of both Alzheimer's disease (AD) patie nts and transgenic A beta PPswe/tg2576 (tg2576) mice. Increasingly, evidenc e 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 A beta levels in brains of tg2576 mice and controls at intervals between 2 and 20 months. In addition, A beta concentrations in plasma and muscle of these animals were also quantified. Results: Quite strikingly, we found that the amount of tg2576 mice brain ap oE was elevated by an average of 45%, relative to the control mice from 2 m onths on. The level of brain apoE soared after 14 months to almost 60% grea ter than the level found in control mice. A beta concentrations in brains b efore 9 months were less than 2 ng/mg of protein, but by 14 months concentr ations rose to 8.7 ng/mg, and by 20 months to 47 ng/mg. In plasma, we noted that the levels of A beta in tg2576 mice declined from above 30 ng/ml prio r to 12 months to 14 ng/ml by 14 months. Histology showed that A beta plaqu es and CAA began to be discernible in the tg2576 mice at about 9 and 20 mon ths of age, respectively. Conclusions: ApoE was immunocytochemically detected in neuritic plaques tha t were positive for thioflavine-S. We suggest that the elevation of brain a poE in tg2576 mice participates in an age-related dysregulation of A beta c learance and signals the start of A beta sequestration during the time of c ognitive dysfunction.