A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss In Vivo

Although amyloid beta(A beta) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features ofADremains unclear. To address the latter, we generated APP transgenic mice expressing the E693 Delta mutation, which causes AD by enhanced A beta oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal A beta oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that A beta oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are A useful model of A beta oligomer-induced pathology in the absence of amyloid plaques.