Tau-network mapping in neurodegenerative diseases and its causal validation through genetic neuromodulation in primate models
Abstract: Recent advances in highly sensitive PET probes have enabled the detection of pathological protein aggregates in neurodegenerative diseases, allowing their localization at the individual patient level (Tagai et al., Neuron. 2021). These developments, however, have revealed that affected brain regions are highly heterogeneous even for patients with similar symptoms, making it challenging to delineate the circuit dysfunctions underlying those symptoms.
In this talk, I will present a novel network mapping approach, in which tau-PET data from individual patients with tauopathies are combined with normative connectome to identify the “core circuits” responsible for specific symptoms. I will present representative examples of this approach (Hori et al., bioRxiv. 2025; Kurose et al., in prep.), and discuss how these findings can be causally validated through genetic neuromodulation in primate models (Hirabayashi et al., Nature Commun. 2024; Neuron 2021). Finally, I will outline our ongoing efforts to translate these insights into neuromodulation strategies aimed at alleviating symptoms in patients with tauopathies.
Visualization of AMPA receptor in living human brain
Abstract: Glutamatergic synapses play central roles in almost all of neuronal functions such as learning, motor and sensory functions. Among glutamate receptors, AMPARs are the “actual mediator” at glutamatergic synapses. Since the cloning of AMPARs approximately two decades ago, enormous number of papers have reported the importance of AMPARs on neuronal functions including diseases. These previous studies proved that AMPAR is the most principal component of neurotransmission. Despite the accumulation of knowledge of physiological roles of AMPARs, its clinical translation is limited. Main reason for this is that we are not currently able to visualize AMPARs in living human brain. Although rodent neuronal disease models are elegant and well characterized, it remains unclear if these animal models fully mimic human disease. Characterization of these diseases with AMPARs in living human brain should provide us biological basis of neuropsychiatric disorders.
We developed novel PET probe for AMPARs, named [11C]K-2. We detected [11C]K-2 signals reflecting specific binding to AMPARs in rat and human (Nature Medicine 2020). Further, we demonstrated that [11C]K-2 image represents cell surface AMPAR which is the physiologically most important fraction (Neuroscience Res 2021, and Ichijo et al. submitted). Using [11C]K-2, we characterized major psychiatric disorders (molecular psychiatry 2024) and epilepsy (Cell Reports Medicine 2023). We are planning to conduct clinical trial to launch [11C]K-2 as a diagnostic of psychiatric disorders. In this lecture, I will go over recent progress of our PET tracers.