October 12, 2021
National Institutes for Quantum Science and Technology
Keio University School of Medicine
Japan Agency for Medical Research and Development
The Department of Functional Brain Imaging at the Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology (QST) (President: Toshio Hirano), led by Makoto Higuchi (Department Head and Group Leader) and Masafumi Shimojo (principal investigator), in collaboration with The Scripps Research Institute in the USA and the Division of Neurology, Department of Internal Medicine at Keio University School of Medicine, has developed an innovative technology. This technology not only accurately captures abnormal neural circuit activity but also images the earliest stages of the accumulation of pathogenic substances causing dementia in the brains of living animals.
Animal brain function relies on the proper processing of information within circuits composed of intricately wired neurons. Furthermore, the cognitive decline observed in many human psychiatric and neurological disorders has been pointed out to be primarily caused by developmental abnormalities or dysfunction in specific circuits. For example, in Alzheimer's disease, a representative form of dementia, it has been suggested that tau protein, considered one of the pathogenic substances, aggregates in the memory-controlling hippocampus from the early stages of the disease. This leads to abnormal activity in circuits connected to the hippocampus, causing a breakdown in brain function. However, imaging the structure and activity of these neural circuits or visualizing the earliest stages of pathogenic protein accumulation non-invasively in animal brains has been technically challenging and had not been achieved until now.
Therefore, in this study, we pioneered the development of a technology to image circuit activity using positron emission tomography (PET). This was achieved by introducing a marker called an "intracerebral reporter," which is not naturally present in the animal's body, into the cells of a specific circuit, and then intravenously injecting an imaging agent that selectively binds to this reporter. Furthermore, we devised an ingenious method by splitting the intracerebral reporter into two parts, linking each part to tau proteins, and expressing them in the brain. This design ensures that the reporter parts only assemble into their complete, PET-imageable form when the tau proteins aggregate. This innovation also enabled the highly sensitive visualization of the earliest stages of tau protein accumulation, which had previously been extremely difficult to detect.
As described above, this technology can serve as a tool to capture various stages of pathophysiology, such as accurately detecting abnormalities in circuit connectivity and activity in the brains of disease model animals, and enabling early detection of the accumulation of pathogenic proteins that cause brain damage. It can be used not only for dementia model animals but also for visualizing defective circuit formation, such as that seen in models of neurodevelopmental disorders. Furthermore, it is expected to be applied in evaluating the efficacy of therapeutic drugs in repairing circuit abnormalities or suppressing abnormal protein accumulation, thereby contributing to the development of treatments for brain diseases.
This research was partially supported by the JST CREST program "Development of new photo-manipulation and imaging methods to elucidate memory structure" (JPMJCR1652), the AMED project "Project for Elucidating the Entire Picture of Brain Function Networks Using Innovative Technologies" (JP19dm0207072), the AMED "Strategic Research Program for Brain Sciences" (JP19dm0107146), and MEXT/JSPS KAKENHI (18H04752, 18K07777). The findings will be published online in the *EMBO Journal* (Impact Factor 11.598) on Tuesday, October 12, 2021, at 7:00 PM (JST).
For the full press release, please see below.