In conventional dementia research, for example, Alzheimer's disease (AD) is mainly caused by the accumulation of amyloid beta (Aβ) and phosphorylated tau (AD pathology), and research aiming to inhibit or eliminate their production has been mainstream. However, it has become clear that even if the administration of the recently developed humanized anti-Aβ antibody Lecanemab suppresses AD pathology, it can slow the progression of dementia, but not completely stop it. This means that once AD pathology progresses, brain function cannot be recovered as it is. Therefore, a completely different approach is needed to recover the function. Therefore, in this study, we focus on "the reservoir function that supports the resilience of the brain." The reservoir function here is the surplus capacity of the brain supported by the plasticity of nerve cells. The representative of R & D has been studying the mechanism of functional recovery after brain and spinal cord injury mainly using primate models. In the process, he found various reservoir functions and tried to develop a method to enhance them. Therefore, as a hypothesis that we want to verify next, we thought that a common reservoir function exists to some extent for chronic neurodegenerative diseases, stress disorders, and acute central nervous system injury. In this research subject, we aim to clarify the substance of the reservoir function of the brain to overcome such neurodegenerative diseases, central damage, and chronic stress as a countermeasure against dementia over the next 20 years, and to verify the above hypothesis and to develop a method to enhance it. There are various layers and mechanisms of action of the reservoir function. In particular, 1. It promotes circuit function that escapes failure in both acute and chronic disorders, 2. It restores damaged cells, 3. It stops the progress of failure in progressive disorders (Fig. 1).
Therefore, in this research project, we will gather research teams specializing in the brain mechanisms of various brain reservoir candidates and work together to develop methods to promote reservoir function as shown in Fig. 1 in various models of disorders. In this research project, the group mainly using rodents will participate in (1) development and demonstration of technology to adjust the threshold of synaptic plasticity as a team of synaptic plasticity and intracellular signaling (Hayashi), identification of signal molecules that are indicators of neuronal "healthiness" and contribute to functional recovery (Watanabe), and enhancement of plasticity by artificial synaptic connectors (Yuzaki, Takeuchi). In addition, (2) identification and characterization of disease-related microglia asa team of inflammation/immunity and glial cells in the brain (Otsuki), loss of microglial diversity in immune inflammation and therapeutic strategies (Wakei), and elucidation of reservoir function in the brain via the brain intestinal axis focusing on the post-translational modification function of serotonylation (Fagarasan). (3)The stress response research team will elucidate the molecular mechanism and regulation of chronic inflammation that underlies stress sensitivity and tolerance (Furuyashiki), and the molecular mechanism of identification and modification of neural circuits related to stress resilience (Uchida). In addition, (4) Takahashi team will work on augmentation by transplantation of brain organoids derived from iPS cells, and (5) Taguchi team will work on augmentation by activation of hippocampal neurogenesis by transplantation of hematopoietic stem cells. These groups will work on clarifying reservoir function and clarifying the mechanism of action of the promotion method targeted by each subinvestigator using multiple mouse models such as AD pathological progression model mice (NL-G-F mice, 5xFAD mice, etc.), chronic cerebral hypoperfusion model assuming vascular dementia, aged model, and chronic stress model mice, and cerebral infarction and spinal cord injury model mice showing acute disorders. The group using non-hominid primates (Macaques and marmosets) (Yamaguchi, Higo, Umeda) will elucidate the induction of large-scale circuit plasticity and its genetic basis in the mature brain by neuromodulation, etc., and verify the effectiveness of the reservoir function enhancement method obtained in rodents in primate models such as aged, cerebral hypoperfusion marmosets, acute cerebral infarction, spinal cord injury, or cerebral hypoperfusion model macaques. In primate models, pathological verification will be carefully conducted in cooperation with experts. The human research group will develop an ensemble brain stimulation method that stimulates multiple brain regions by phase modulation as neuromodulation, and aim to enhance reservoir function (Mima, Koganemaru). The Matsumoto team will also develop an electroencephalographic physiological index of the cognitive resilience enhancement effect of dual motor and cognitive tasks based on the cohort study. Based on MRI cohorts of elderly patients, including those with dementia, MRI imaging of human postmortem brains, and integrated studies of tissue and molecular information by optical and mass microscopy, the Hanakawa team will explore the nature of the human brain's resilience/reservoir function, which enables cognitive function to be maintained against aging, and provide the information obtained to other groups.
In the rodent group, promising reservoir functions will be identified in 2024 – 27, and augmentation methods will be developed in dementia models and cerebral infarction/spinal cord injury model mice by 2030. In particular, we will focus on whether augmentation methods in AD model mice improve function while AD pathology progresses, or stop or eliminate AD pathology. Then, we will verify in primate models and obtain a proof of concept (PoC). On the other hand, we will elucidate the mechanism of augmentation methods that are promising in human studies in rodent and primate models. In this way, the aim of this study is to link the results in rodents and humans to the acquisition of PoC including verification in primate models. This will lead to the acquisition of PoC in preclinical primate models by 2035 and human clinical trials by 2040 for many issues. For this purpose, since the research of each team may see both sides of the same phenomenon, we will promote collaboration and joint research among each team.
