4 Year PhD in Neuroscience. (360G-Wellcome-102267_Z_13_Z)

The molecular mechanisms that control the formation and growth of synapses are well understood. However, much less is known about how synapses are maintained in the adult brain and how synapse loss and dysfunction is triggered in neurodegenerative conditions, such as Alzheimer's disease (AD). The Wnt signalling pathway modulates neuronal circuit formation during development. Recent studies suggest that deficits in this pathway contribute to AD pathogenesis. We have demonstrated that Amyloid beta (AB), the main component of Amyloid plaques, increases the expression of Dickkopf-1 (Dkk1), a secreted Wnt antagonist that blocks Wnt function by binding to the Wnt co-receptor LRP6. Blockade of Dkk1 with neutralizing antibodies, protects synapses from AB-mediated toxicity. Thus, impaired Wnt signalling results in synapse loss and may contribute to synapse failure by AB. A genome wide association study has demonstrated a link between a LRP6 variant (LRP6-Val), with decreased Wnt activity, and late-onset AD. However, the impact of this variant on synapse maintenance and plasticity has not been examined. In this project, we will investigate how the LRP6 variant affects synapse integrity using a combination of cellular and electrophysiological approaches. Our studies will contribute to a better understanding of how synapses become vulnerable in AD.