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

ABSTRACT: Oligomers of intracellular amyloid ? protein (A?) 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? oligomers only. We have now developed a novel AD model mouse, an A?-GFP transgenic mouse (A?-GFP Tg), that expresses the GFP-fused human A?1-42 protein, which forms only A? 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?-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?-GFP fusion protein is bioactive and highly toxic, and induces the similar synaptic dysfunctions as the naturally generated A? oligomer derived from postmortem AD patient brains and synthetic A? oligomers. Thus, A?-GFP Tg mouse is a new tool specialized to analyze the function of A? oligomers in vivo and to find subtle changes in synapses in early symptoms of AD.

SUBMITTER: Ochiishi T 

PROVIDER: S-EPMC6874556 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature