Novel aspects of accumulation dynamics and Aβ composition in transgenic models of AD

A homogeneous time-resolved fluorescence immunoassay for detection of β-amyloid (Aβ) peptides has been adapted for quantification of Aβ(40) and Aβ(42) accumulation in brains of APP695SWE transgenic mice. These over-express human βAPPswe, β-amyloid precursor protein (β-APP) containing the K670N/M671L ‘Swedish’ familial Alzheimer’s disease (FAD) mutation. Both peptides start to accumulate in this line from about 260 to 280 days of age. Co-expression of a human presenilin-1 (PS1) transgene containing the A246E FAD mutation accelerates deposition and also favors—at least initially—accumulation of Aβ(42) so that the Aβ(2):Aβ(40) ratio of peptides from 7- to 12-month-old APP695SWE × PS1A246E animals is significantly elevated above that observed throughout the lifetime of APP695SWE mice. These findings, supported by parallel immunohistochemical staining and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry data, offer important longitudinal characterization of two mouse models of cerebral amyloidosis. Application of the same extraction and quantitation procedures to samples of temporal cortex from AD sufferers indicates however that Aβ(40) is only a minor component of β-amyloid in humans.