Planar cell polarity signaling components are a direct target of β-amyloid-associated degeneration of glutamatergic synapses

Bo Feng, Andiara E. Freitas, Lilach Gorodetski, Jingyi Wang, Runyi Tian, Yeo Rang Lee, Akumbir S. Grewal, Yimin Zou

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The signaling pathway directly controlling the maintenance of adult glutamatergic synapses has not been well understood. Planar cell polarity (PCP) signaling components were recently shown to play essential roles in the formation of glutamatergic synapses. Here, we show that they are localized in the adult synapses and are essential for their maintenance. Synapse loss at early stages of Alzheimer's disease is thought to be induced by β-amyloid (Aβ) pathology. We found that oligomeric Aβ binds to Celsr3 and assists Vangl2 in disassembling synapses. Moreover, a Wnt receptor and regulator of PCP signaling, Ryk, is also required for Aβ-induced synapse loss. In the 5XFAD mouse model of Alzheimer's disease, Ryk conditional knockout or a function-blocking monoclonal Ryk antibody protected synapses and preserved cognitive function. We propose that tipping of the fine balance of Wnt/PCP signaling components in glutamatergic synapses may cause synapse degeneration in neurodegenerative disorders with Aβ pathology.

Original languageEnglish
Article numbereabh2307
JournalScience advances
Volume7
Issue number34
DOIs
StatePublished - Aug 2021
Externally publishedYes

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