The Evolution of A β Peptide Burden in the APP23 Transgenic Mice: Implications for A β Deposition in Alzheimer Disease

Background High levels of A β in the cerebral cortex distinguish demented Alzheimer’s disease (AD) from nondemented elderly individuals, suggesting that decreased amyloid-beta (A β ) peptide clearance from the brain is a key precipitating factor in AD. Materials and Methods The levels of A β in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunosorbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immunocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellular amyloid precursor protein (APP) deposits in the APP23 Tg mice. Results No significant differences were found in the plasma levels of A β between the APP23 Tg and control mice from 2–20 months of age. In contrast, soluble A β levels in the brain were continually elevated, increasing 4-fold at 2 months and 33-fold in the APP23 Tg mice at 20 months of age when compared to the control mice. Soluble A β 42 was about 60% higher than A β 40. In the APP23 Tg mice, insoluble A β 40 remained at basal levels in the brain until 9 months and then rose to 680 µg / g cortex by 20 months. Insoluble A β 40 was negligible in non-Tg mice at all ages. Insoluble A β 42 in APP23 Tg mice rose to 60 µg / g cortex at 20 months, representing 24 times the control A β 42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming substantially higher by 20 months. ApoE colocalized with A β in the plaques. Beta-amyloid precursor protein ( β APP) deposits were detected within the neuronal cytoplasm from 4 months of age onward. Amyloid angiopathy in the APP23 Tg mice increased markedly with age, being by far more severe than in the Tg2576 mice. Conclusions We suggest that the APP23 Tg mouse may develop an earlier blockage in A β clearance than the Tg2576 mice, resulting in a more severe accumulation of A β in the perivascular drainage pathways and in the brain. Both Tg mice reflect decreased A β elimination and as models for the amyloid cascade they are useful to study AD pathophysiology and therapy.