Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease

Wnt signalling is an essential signalling system in neurogenesis, with a crucial role in synaptic plasticity and neuronal survival, processes that are disrupted in Alzheimer's disease (AD). Within this network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical Wnt-planar cell polarity (Wnt/PCP) pathway in AD remains to be determined. This study investigates the role of ROR2, a Wnt/PCP co-receptor, in synaptogenesis. We demonstrate that WNT5A-ROR2 signalling activates the JNK pathway, leading to synapse loss in mature neurons. This effect mirrors the synaptotoxic actions of Aβ1-42 and DKK1, which are elevated in AD. Notably, blocking ROR2 and JNK mitigates Aβ1-42 and DKK1-induced synapse loss, suggesting their dependence on ROR2. In induced pluripotent stem cell (iPSC)-derived cortical neurons carrying a PSEN1 mutation, known to increase the Aβ42/40 ratio, we observed increased WNT5A-ROR2 clustering and reduced numbers of synapses. Inhibiting ROR2 or JNK partially rescued synaptogenesis in these neurons. These findings suggest that, unlike the Wnt/β-catenin pathway, the Wnt/PCP-ROR2 signalling pathway can operate in a feedback loop with Aβ1-42 to enhance JNK signalling and contribute to synapse loss in AD.