A new study, published in Science, suggests that deficient Wnt signalling may contribute to synapse loss and cognitive decline in Alzheimer’s disease (AD). A specific variant of the LRP6 receptor (LRP6-Val), with reduced Wnt signalling, is linked to late-onset AD. Researchers studied the impact of LRP6-Val on AD brain using knock-in mice.
The study found that neurons from these mice do not respond to a specific ligand (Wnt7a) that promotes synaptic assembly. This results in structural and functional defects in the mice’s synapses, which become more pronounced as the mice age. Additionally, when these LRP6-Val mice are crossed with a specific AD model, they exhibit exacerbated synapse loss around plaques. Overall, the study suggests that LRP6-Val plays a previously unidentified role in synapse vulnerability during aging and AD. These findings uncover new mechanisms behind the link between synapse loss and cognitive decline in Alzheimer’s disease and may provide new avenues for treatment research.
Wnt signalling, LRP6, and synapse loss
The link between memory impairment and synapse degeneration in Alzheimer’s disease is well established. Synaptic changes occur early in the disease before the formation of amyloid-beta (Aβ) plaques and neuronal loss. However, the molecular mechanisms that lead to synapse dysfunction and loss in AD remain poorly understood. The Wnt signalling pathway (Figure 1A) is a critical aspect of synapse function and stability, and research suggests that it may be impaired in Alzheimer’s disease.
Wnt ligands and their receptors are present in many brain areas affected by AD, including the hippocampus, but it is not fully understood how they function in neurons. Studies have shown that the Wnt signalling pathway plays a crucial role in both synaptogenesis during development and synapse integrity in the adult brain. Evidence suggests that the Wnt signalling pathway is compromised in AD through the elevation of the secreted Wnt antagonist, Dickkopf-1 (Dkk1), in the brains of AD patients and AD mouse models.
Additionally, genetic variants of the Wnt co-receptor LRP6 have been linked to late-onset AD. The LRP6-Val variant (Figure 1B) in particular reduces Wnt signalling in cell lines in response to a Wnt ligand, but further research is needed to understand its impact on brain development, neuronal connectivity, and amyloid pathology in AD. Overall, the Wnt signalling pathway may be a potential target for AD treatment.
To investigate the impact of the LRP6-Val variant on synapse formation and its role in the development of Alzheimer’s disease researchers first expressed LRP6-Val in cultured hippocampal neurons and found that it reduced pre- and postsynaptic sites, and was unable to stimulate synaptic assembly. They then generated a knock-in mouse model and found that Lrp6-val KI mice develop normally, and that LRP6-Val does not affect its synaptic localization.
They found that adult Lrp6-val mice had reduced spine head width and compromised neurotransmitter release, and these effects become more severe with age. They also found that Lrp6-val variant impairs basal synaptic transmission and neurotransmitter release probability, and that Lrp6-val mice have fewer and smaller presynaptic boutons, and fewer synaptic vesicles at presynaptic terminals. Carrying one allele of the Lrp6-val variant also confers postsynaptic vulnerability.
They also found that Wnt signalling was compromised with age in Lrp6-val mice and that Lrp6-val neurons did not respond to Wnt7a or Wnt3a, which are involved in presynaptic assembly. Additionally, they showed that the presence of LRP6-Val impairs the formation of the Wnt-induced LRP6-Fz5 complex, which is required for signalling. They also showed that downstream signalling was affected by the presence of LRP6-Val and that the Lrp6-val variant does not affect plaque load in NL-G-F mice, a mouse model of Alzheimer’s disease. Overall, this suggests that the Lrp6-val variant impairs synaptic formation and neurotransmitter release and may contribute to the development of AD.
This study provides new evidence of the role of LRP6-Val in synapse loss and cognitive decline in Alzheimer’s disease. The findings demonstrate the importance of Wnt signalling in synapse formation and suggest that LRP6-Val may be a potential target for AD treatment. These results open the way for further research to understand the molecular mechanisms and potential therapeutic strategies for AD.