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bioRxiv · 10.1101/2024.07.16.603668

Amyloid-β can activate JNK signalling via WNT-5A/ROR2 to reduce synapse formation in Alzheimer's disease.

Scholpp, S.·Fang, K.·Pishva, E.·Piers, T.
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Abstract

Wnt signalling is an essential signalling system in neurogenesis, and recent studies have highlighted the critical role of this signalling network in regulating synaptic plasticity, neuronal survival, and neurogenesis, processes that are disrupted in Alzheimers disease (AD). From the Wnt network, the Wnt/{beta}-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical pathway, which operates independently of {beta}-catenin and involves the planar cell polarity (PCP), remains to be determined in AD. In this work, we analyse the function of the orphan receptor tyrosine kinase ROR2, an essential co-receptor of the Wnt/PCP signalling pathway. We find that activation of WNT-5A/ROR2 signalling activates JNK signalling, reducing pre- and postsynaptic clusters on neurites in mature SH-SY5Y neurons. This observation is similar to SH-SY5Y neurons treated with the Amyloid-{beta} peptide A{beta}1-42 or DKK1, which are both increased in AD. Surprisingly, the effect of A{beta}1-42 and DKK1 signalling on synaptogenesis can be mitigated by blocking ROR2 and JNK signalling, suggesting that A{beta} and DKK1 signalling depends on ROR2/JNK signalling. Finally, we find an increase of WNT-5A/ROR2 clusters on neurites of iPSC-derived cortical neurons carrying the PSEN1 A75V mutation, known to enhance the pathological A{beta}42/40 ratio. Simultaneously, the number of pre- and post-synaptic clusters decreased in the mutant line. Inhibition of ROR2/JNK signalling in PSEN1A75V cortical neurons partially rescues the reduction in synaptogenesis, suggesting that ROR2 signalling may act in a positive feedback loop with A{beta}1-42 and DKK1 signalling to augment JNK signalling as seen in AD.

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Scholpp, S., Fang, K., Pishva, E., Piers, T.. 2024-07-17. Amyloid-β can activate JNK signalling via WNT-5A/ROR2 to reduce synapse formation in Alzheimer's disease.. https://doi.org/10.1101/2024.07.16.603668

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