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

Synapse loss strongly correlates with memory impairment in Alzheimer’s disease (AD). However, the underlying mechanisms are poorly understood. Deficient Wnt signalling, a pathway required for synapse integrity in the mature brain, contributes to synapse degeneration in AD. A variant of LRP6 (LRP6-Val), which has a single amino acid substitution of isoleucine to valine in the fourth extracellular β-propeller domain, reduces Wnt signalling and is linked to late-onset AD. However, the impact of LRP6-Val on synapses in the ageing brain and AD has not been addressed. Our lab generated a novel knock-in mouse model carrying the Lrp6-val variant. My analyses of these mice revealed an age-dependent decrease in excitatory synapse number and a concomitant increase in inhibitory synapse number. Furthermore, microglia number is elevated in aged Lrp6-val mice. Examination of the mechanism by which Lrp6-val induces synaptic defects revealed that neurons from Lrp6-val mice do not respond to Wnt7a to promote synapse formation. Finally, to investigate the impact of Lrp6-val in AD, Lrp6-val mice were crossed to the NL-G-F AD model. Lrp6-val does not affect Aβ levels or plaque load. However, synapse loss is exacerbated around the plaques. My novel results uncover a role for the Lrp6-val variant in the ageing and AD brain. I demonstrate that Lrp6-val reduces the number of excitatory synapses and increases inhibitory synapse number with age and enhances synapse vulnerability in AD. Moreover, these findings demonstrate that a single amino acid substitution in the fourth extracellular β-propeller domain impairs the ability of Wnt7a to promote synapse formation, suggesting that Wnt7a could interact with this region. Thus, my work reveals the function of a variant of Lrp6 associated with AD in synapse degeneration in ageing and AD