Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease

The accumulation of amyloid beta protein (A beta) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in A beta begin at 6-7 months as SDS-insoluble forms of A beta 42 and A beta 40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. As insoluble A beta appears, SDS-soluble A beta decreases slightly, suggesting that it may be converting to an insoluble form. Our data indicate that it is full-length unmodified A beta that accumulates initially in Tg2576 brain. SDS-resistant A beta oligomers and most A beta species that are N-terminally truncated or modified develop only in older Tg2576 mice, in which they are present at levels far lower than in human AD brain. Between 6 and 10 months, when SDS-insoluble A beta 42 and A beta 40 are easily detected in every animal, histopathology is minimal because only isolated A beta cores can be identified. By 12 months, diffuse plaques are evident. From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted A beta 42 and A beta 40 increase to levels like those observed in AD brains. Coincident with the marked deposition of A beta in brain, there is a decrease in CSF A beta and a substantial, highly significant decrease in plasma A beta. If a similar decline occurs in human plasma, it is possible that measurement of plasma A beta may be useful as a premorbid biomarker for AD.