– Expectation for elucidating the pathogenic mechanisms and developing methods to prevent and improve cognitive impairment –
Researchers: OCHIISHI Tomoyo, Senior Researcher, DOI Motomichi, assigned to the group, and EBIHARA Tatsuhiko, assigned to the group, Molecular Neurobiology Group, Biomedical Research Institute, and KIYOSUE Kazuyuki, Leader, Functional Biomolecular Research Group of the research institute
In collaboration with Uekusa Gakuen University and Juntendo University, the researchers have developed a novel mouse model of Alzheimer's disease (AD) that expresses only oligomers of amyloid-β protein (Aβ), one of the causative factors of AD, in neurons and exhibits early stage of AD.
Development of Aβ-GFP mice expressing oligomers of Aβ-GFP fusion protein (schematic diagram, left). Aβ oligomers are strongly expressed in neurons in the hippocampus and the cerebral cortex of the brain (right).
AD has been thought to be triggered by the aggregation and accumulation of Aβ outside the neurons. In order to reproduce this condition, various transgenic mice overexpressing amyloid precursor proteins (APPs), a precursor of Aβ, have been generated. However, APP also overexpresses peptides other than Aβ, making it an unlikely model for AD. On the other hand, it has recently been suggested that Aβ oligomers accumulate inside neurons prior to the accumulation of senile plaques and are contributed to the pathogenesis of AD. In model mice thus far, however, it is very difficult to discern which pathological feature is induced by Aβ oligomers and which by extracellular aggregates, and no suitable mouse model had been developed to analyze oligomer toxicity.
The AD model mice developed in this study are transgenic mice (Aβ-GFP mice) that express Aβ-GFP fusion protein. Aβ-GFP mice express highly toxic Aβ1-42 only so there is no need to consider the effects of bioactive peptides other than Aβ, which is produced by APP overexpression. In addition, because Aβ-GFP fusion protein has no extracellularly secreted signal sequence, Aβ oligomers accumulate only inside the cells. In the brain, Aβ oligomers are strongly expressed in neurons in the hippocampus and the cerebral cortex.
The researchers will administer candidate substances for the prevention and treatment of AD to Aβ-GFP mice and search for drug candidates that are effective in improving cognitive function. They will also examine the effects of exercise and other activities that are believed to improve cognitive function in these mice, and promote research to elucidate the mechanisms of cognitive function improvement in the body and to prevent AD.