Soluble Aβ species are toxic in cell culture.74 APP transgenic mice have provided strong circumstantial evidence for the toxicity of Aβ oligomers in vivo by showing that many pathological and functional changes in mice occur before the appearance of plaque pathology. For example, a series of studies in PDAPP mice demonstrated that volume loss and other anatomic changes in the dentate gyrus are present in 100-day-old mice well before plaque deposition.75,76 Tg2576 mice also exhibit electro-physiological and behavioral changes months before plaque deposition,77 and axonal swellings may be present in Tg2576 mice for up to a year before amyloid deposition.78 Behavioral and electrophysiological changes have been described in other lines of APP mice before amyloid deposition as well.30,79,80 The finding of pathophysiological changes in PS1 FAD mutant mice (discussed previously) that have elevated Aβ42 but no plaques is also consistent with a toxic role for soluble forms of Aβ.
