Synapse loss is an early event in Alzheimer’s 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 dissembling synapses by disrupting the intercellular Celsr3/Frizzled3-Celsr3 complexes, 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 Alzheimer’s disease, 5XFAD, where conditional Ryk knockout protected synapses and preserved cognitive functions. 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 Alzheimer’s disease patients, our results suggest that the imbalance of PCP signaling in these patients may contribute to synapse loss in Alzheimer’s disease and manipulating Wnt/PCP signaling may preserve synapses and cognitive function.
bioRxiv Subject Collection: Neuroscience