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bioRxiv · 10.1101/2020.09.09.273011

Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling

Feng, B.·Freitas, A.·Tian, R.·Lee, Y. R.·Grewal, A.·Wang, J.·Zou, Y.
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Abstract

Synapse loss is an early event in Alzheimers disease and is thought to be associated with amyloid pathology and caused by Amyloid {beta} (A{beta}) oligomers. Whether and how A{beta} oligomers directly target signaling pathways for glutamatergic synapse maintenance is unknown. Glutamatergic synapse development is controlled by the opposing functions of Celsr3 and Vangl2, core components of the Wnt/planar cell polarity (PCP) signaling pathway, functioning directly in the synapses. Celsr3 promotes synapse formation, whereas Vangl2 inhibits synapse formation. Here we show that oligomeric A{beta} binds to Celsr3 and assists Vangl2 in disassembling synapses by disrupting the intercellular Celsr3/Frizzled3-Celsr3 complex, essential for PCP signaling. Together with Vangl2, a Wnt receptor, Ryk, is also required for A{beta} oligomer-induced synapse loss in a mouse model of Alzheimers disease, 5XFAD, where conditional Ryk knockout protected synapses and preserved cognitive function. Our study reveals a fine balance of Wnt/PCP signaling components in glutamatergic synapse maintenance and suggests that overproduced A{beta} oligomers may lead to excessive synapse loss by tipping this balance. Together with previous reports that an inhibitor of Wnt/Ryk signaling, WIF1, is found reduced in Alzheimers disease patients, our results suggest that the imbalance of PCP signaling in these patients may contribute to synapse loss in Alzheimers disease and manipulating Wnt/PCP signaling may preserve synapses and cognitive function.

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Feng, B., Freitas, A., Tian, R., Lee, Y. R., Grewal, A., Wang, J., Zou, Y.. 2020-09-09. Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling. https://doi.org/10.1101/2020.09.09.273011

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