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bioRxiv · 10.1101/2022.04.06.487208

A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during ageing and in Alzheimer's disease

Jones, M. E.·Buechler, J.·Dufor, T.·Boroviak, K.·Metzakopian, E.·Gibb, A.·Salinas, P. C.
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Abstract

Synapse loss strongly correlates with cognitive decline in Alzheimers Disease (AD), but the underlying mechanisms are poorly understood. Studies suggest that deficient Wnt signalling, a pathway required for neuronal connectivity, contributes to synapse dysfunction and loss in AD. Consistent with this idea, a variant of Lrp6, (Lrp6-val), which confers reduced Wnt signalling, has been linked to late onset AD. However, the impact of Lrp6-val on synapses in the healthy and AD brain has not been examined. Using CRISPR/Cas9 genome editing, we generated a novel knock-in mouse model carrying this Lrp6 variant to study its role in synaptic integrity. Lrp6-val mice develop normally and do not exhibit morphological brain abnormalities. Hippocampal neurons from Lrp6-val mice do not respond to Wnt7a, a Wnt ligand that promotes synaptic assembly through the Frizzled-5 (Fz5) receptor. Activation of the Wnt pathway by Wnt ligands leads to the formation of a complex between LRP6 and Fz5. In contrast, LRP6-Val impairs the formation of the LRP6-Fz5 complex elicited by Wnt7a, as detected by proximity ligation assay (PLA). We demonstrate that Lrp6-val mice exhibit structural and functional synaptic defects that become more pronounced with age, consistent with decreased canonical Wnt signalling during ageing. To investigate the contribution of this variant to AD, Lrp6-val mice were crossed to hAPPNL-G-F/NL-G-F (NL-G-F), a knock-in AD mouse model. The presence of the Lrp6-val variant significantly exacerbates synapse loss around amyloid-{beta} plaques in NL-G-F mice. Our findings uncover a novel role for the Lrp6-val variant in synapse vulnerability during ageing and its contribution to synapse degeneration in AD.

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Jones, M. E., Buechler, J., Dufor, T., Boroviak, K., Metzakopian, E., Gibb, A., Salinas, P. C.. 2022-04-08. A genetic variant of the Wnt receptor LRP6 accelerates synapse degeneration during ageing and in Alzheimer's disease. https://doi.org/10.1101/2022.04.06.487208

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