Contribution of a genetic variant of the Wnt receptor LRP6 to synapse vulnerability in the ageing hippocampus

Synapse dysfunction and loss represent key pathological hallmarks of Alzheimer's disease (AD). Wnt signalling, in particular through the Wnt co-receptor LRP6, has a critical role in maintaining the structural and functional integrity of synaptic connections in the adult brain. LRP6 dysfunction and deficient Wnt signalling compromise synaptic circuits during ageing, contributing to AD pathogenesis. Wnt signalling has been implicated in AD through a genetic link: A common variant of LRP6 (LRP6-Val) based on a single-nucleotide polymorphism (SNP) confers reduced Wnt signalling activity in cell lines and is associated with an increased risk for late-onset AD. However, it is unknown whether LRP6-Val has a functional impact on synapses in the brain. To investigate the LRP6-Val variant in a physiological context, a novel knock-in mouse model was generated for this study. I examined the structure and function of excitatory hippocampal synapses as well as hippocampus-dependent memory function, using a multidisciplinary approach combining cell biology, imaging, electrophysiological and behavioural studies. My findings demonstrate that the LRP6-Val variant compromises Wnt signalling in an age-dependent manner, leading to pre- and postsynaptic structural and functional defects in the ageing hippocampus. Shrinkage of presynaptic terminals and dendritic spines is accompanied by reduced neurotransmitter release. Upregulation of astrocytes and microglia suggests concomitant neuroinflammation, which may further contribute to synaptic damage. However, global synaptic transmission is preserved and memory function remains unaffected in LRP6-Val knock-in mice up to 14 months of age, possibly due to a homeostatic adjustment of synapse density. Synaptic defects caused by LRP6-Val may exacerbate synapse vulnerability to further toxic insults with advancing age, increasing the risk of a pathological transition towards AD. The results of this study advance our understanding of the role of LRP6-mediated Wnt signalling for synapse maintenance during ageing and strengthen the link between aberrant Wnt signalling, synaptic degeneration and Alzheimer's disease.