Dkk1-Wnt signalling pathway in synapse degeneration: implication for early stages of Alzheimer's disease

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Alzheimer's disease (AD) is a neurodegenerative condition characterised by a failing memory and loss of the ability to form and retain new memories. These cognitive features are recognised to be dependent on changes in the number and strength of neuronal contacts called synapses. In AD patients, a progressive cognitive decline and deposition of Amyloid-Beta (A-Beta) plaques in the brain are observed. Work from many labs has demonstrated that A-Beta induces neuronal cell death. However, cognitive decline is best correlated with the loss and dysfunction of synapses. Thus, protection of synapses against vulnerability could provide an avenue for early intervention in AD before considerable cognitive decline is evident.For many years, our lab has been studying the mechanisms that control synapse formation, growth and maturation in the mammalian brain by focusing on the function of a family of secreted proteins called Wnts. We discovered that Wnts promote the formation of synapses during development and are also required for synapse integrity in the adult brain. Studies from our lab and others strongly suggest that A-Beta compromises the function of Wnt proteins. Indeed, we discovered that A-Beta promotes the synthesis of Dickkopf-1 (Dkk1), a secreted Wnt antagonist and this protein mediates the toxic effect(s) of A-Beta on brain synapses. We recently developed a mouse model to study the function of Dkk1. Using these mice, we demonstrated that Dkk1 induces the loss and dysfunction of synapses in the hippocampus, a brain area crucial for learning and memory. Consistently, Dkk1 expression in the adult brain induces long-term memory defects. The proposed programme of research builds upon these findings. Our main aim is to identify molecules that contribute to synapse degeneration induced by Dkk1. We will employ a multidisciplinary strategy that combines cellular, electrophysiological and behavioural approaches to enhance understanding of these devastating pathological processes.Our studies will lead to a better understanding of the principles that control synapse integrity and the mechanisms that trigger synapse vulnerability. Thus, our findings will permit the development of therapeutic strategies aimed at ameliorating the symptoms and possibly preventing the progression of cognitive decline at the early stages of AD. Our findings would also contribute to the identification of biomarkers for the early detection of AD.