New Alzheimer's disease model mouse specialized for analyzing the function and toxicity of intraneuronal Amyloid β oligomers

Oligomers of intracellular amyloid beta protein (A beta) are strongly cytotoxic and play crucial roles in synaptic transmission and cognitive function in Alzheimer's disease (AD). However, there is currently no AD model mouse in which to specifically analyze the function of A beta oligomers only. We have now developed a novel AD model mouse, an A beta-GFP transgenic mouse (A beta-GFP Tg), that expresses the GFP-fused human A beta(1-42) protein, which forms only A beta oligomers within neurons throughout their life. The fusion proteins are expressed mainly in the hippocampal CA1-CA2 region and cerebral cortex, and are not secreted extracellularly. The A beta-GFP Tg mice exhibit increased tau phosphorylation, altered spine morphology, decreased expressions of the GluN2B receptor and neuroligin in synaptic regions, attenuated hippocampal long-term potentiation, and impaired object recognition memory compared with non-Tg littermates. Interestingly, these dysfunctions have already appeared in 2-3-months-old animals. The A beta-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated A beta oligomer derived from postmortem AD patient brains and synthetic A beta oligomers. Thus, A beta-GFP Tg mouse is a new tool specialized to analyze the function of A beta oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.