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

Abstract

Synapse loss strongly correlates with cognitive decline in Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Deficient Wnt signaling contributes to synapse dysfunction and loss in AD. Consistently, a variant of the <i>LRP6</i> receptor, (<i>LRP6-Val</i>), with reduced Wnt signaling, is linked to late-onset AD. However, the impact of <i>LRP6-Val</i> on the healthy and AD brain has not been examined. Knock-in mice, generated by gene editing, carrying this <i>Lrp6</i> variant develop normally. However, neurons from <i>Lrp6-val</i> mice do not respond to Wnt7a, a ligand that promotes synaptic assembly through the Frizzled-5 receptor. Wnt7a stimulates the formation of the low-density lipoprotein receptor-related protein 6 (LRP6)-Frizzled-5 complex but not if LRP6-Val is present. <i>Lrp6-val</i> mice exhibit structural and functional synaptic defects that become pronounced with age. <i>Lrp6-val</i> mice present exacerbated synapse loss around plaques when crossed to the <i>NL-G-F</i> AD model. Our findings uncover a previously unidentified role for <i>Lrp6-val</i> in synapse vulnerability during aging and AD.