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所：中⽥記念ホール 統合脳機能研究センター６階

脳研究所

Mechanisms of glutamatergic synapse degeneration in brain aging
Yimin Zou
Professor
Department of Neurobiology, School of Biological Sciences,
University of California, San Diego. USA
Brain aging is a universal phenomenon in all mammalian species and has many manifestations,including structural changes and decline of functions. The synapses are the main computational unitof neural circuits. Reduction of synaptic numbers and decline of synaptic functions, which occur inhealthy aging, are closely correlated with brain aging and may be the underlying mechanism ofdecline of brain function. Work from our lab showed that the planar cell polarity (PCP) signaling
pathway plays an essential and direct role in glutamatergic synapses formation in development andglutamatergic synapse maintenance in adulthood (Thakar et al., 2017) (Zou, 2020) (Ban et al., 2021)(Feng et al., 2021) (Freitas et al., 2023). The PCP proteins are localized in the developing and adultsynapses and interact with synaptic scaffold proteins and glutamate receptors and are responsible
for the formation and stability of the vast majority of glutamatergic synapses in the brain.
Neurodegenerative disorders, such as Alzheimer's disease (AD), are a form of accelerated aging andare thought to start with synapse degeneration. Our lab found that planar cell polarity is the key
signaling mechanism for synapse maintenance and the direct target for amyloid β induced synapse
degeneration (Feng et al., 2021). Oligomeric Aβ binds to Celsr3 and weakens the interaction between
Celsr3 and Frizzled3 and assists Vangl2 in disassembling synapses. A regulator of PCP signaling, Ryk,is also required for Aβ-induced synapse loss functioning together with Vangl2. In the 5XFAD mousemodel of Alzheimerʼs disease, Ryk conditional knockout in neurons or intracerebroventricular infusionof a function-blocking monoclonal Ryk antibody protected synapses and preserved cognitive function(Feng et al., 2021). In healthy humans, Frizzled3 express level declines with age whereas Vangl2
expression level increases, suggest that the PCP proteins may also mediate age-related synapse
decline in healthy aging (Folke et al., 2019). Therefore, the PCP pathway has emerged as a key
regulatory mechanism for synapse decline in both accelerated and heathy brain aging and provides
novel target to understand and intervene brain aging.
References
Ban, Y., Yu, T., Feng, B., Lorenz, C., Wang, X., Baker, C., and Zou, Y. (2021). Prickle promotes the formation and maintenance ofglutamatergic synapses by stabilizing the intercellular planar cell polarity complex. Sci Adv 7, eabh2974.
Feng, B., Freitas, A.E., Gorodetski, L., Wang, J., Tian, R., Lee, Y.R., Grewal, A.S., and Zou, Y. (2021). Planar cell polarity signaling
components are a direct target of beta-amyloid-associated degeneration of glutamatergic synapses. Sci Adv 7.
Folke, J., Pakkenberg, B., and Brudek, T. (2019). Impaired Wnt Signaling in the Prefrontal Cortex of Alzheimer's Disease. Mol
Neurobiol 56, 873-891.
Freitas, A.E., Gorodetski, L., Lim, W.L., and Zou, Y. (2023). Emerging roles of planar cell polarity proteins in glutamatergic synapse
formation, maintenance and function in health and disease. Dev Dyn.
Thakar, S., Wang, L., Yu, T., Ye, M., Onishi, K., Scott, J., Qi, J., Fernandes, C., Han, X., Yates, J.R., 3rd, et al. (2017). Evidence foropposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. Proc Natl Acad Sci U S A 114, E610-E618.
Zou, Y. (2020). Breaking symmetry - cell polarity signaling pathways in growth cone guidance and synapse formation. Curr Opin
Neurobiol 63, 77-86.

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（担当：脳研究所 細胞病態学分野）