2023年8月25日（金）11:00〜12:00

Yimin Zou

Professor
Department of Neurobiology, School of Biological Sciences,
University of California, San Diego. USA

英語

"Mechanisms of glutamatergic synapse degeneration in brain aging"

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 unit of neural circuits. Reduction of synaptic numbers and decline of synaptic functions, which occur in healthy aging, are closely correlated with brain aging and may be the underlying mechanism of decline 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 and glutamatergic 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 adult synapses 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 and are 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 mouse model of Alzheimer's disease, Ryk conditional knockout in neurons or intracerebroventricular infusion of 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 of glutamatergic 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 for opposing roles of Celsr3 and Vangl2 in glutamatergic synapse formation. Proc Natl Acad Sci USA 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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