The evolution of A beta peptide burden in the APP23 transgenic mice: Implications for A beta deposition in Alzheimer disease

Background: High levels of A beta in the cerebral cortex distinguish dement ed Alzheimer's disease (AD) from nondemented elderly individuals, suggestin g that decreased amyloid-beta (A beta) peptide clearance from the brain is a key precipitating factor in AD. Materials and Methods: The levels of A beta in brain and plasma as well as apolipoprotein E (ApoE) in brain were investigated by enzyme-linked immunos orbent assay (ELISA) and Western blotting at various times during the life span of the APP23 transgenic (Tg) and control mice. Histochemistry and immu nocytochemistry were used to assess the morphologic characteristics of the brain parenchymal and cerebrovascular amyloid deposits and the intracellula r amyloid precursor protein (A-PP) deposits in the APP23 Tg mice. Results: No significant differences were found in the plasma levels of A be ta between the APP23 Tg; and control mice from 2-20 months of age. In contr ast, soluble A beta levels in the brain were continually elevated, increasi ng 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 beta 42 was about 60% higher t han A beta 40. In the APP23 Tg mice, insoluble A beta 40 remained at basal levels in the brain until 9 months and then rose to 680 mug/g cortex by 20 months. Insoluble A beta 40 was negligible in non-Tg mice at all ages. Inso luble A beta 42 in APP23 Tg mice rose to 60 mug/g cortex at 20 months, repr esenting 24 times the control A beta 42 levels. Elevated levels of ApoE in the brain were observed in the APP23 Tg mice at 2 months of age, becoming s ubstantially higher by 20 months. ApoE colocalized with A beta in the plaqu es. Beta-amyloid precursor protein (beta 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 tha n in the Tg2576 mice. Conclusions: We suggest that the APP23 Tg mouse may develop an earlier bloc kage in A beta clearance than the Tg2576 mice, resulting in a more severe a ccumulation of A beta in the perivascular drainage pathways and in the brai n. Both Tg mice reflect decreased A beta elimination and as models for the amyloid cascade they are useful to study AD pathophysiology and therapy.