The role of DKK3 in synapse dynamics in the adult hippocampus and in Alzheimer’s Disease

Synaptic loss highly correlates with cognitive decline in Alzheimer’s Disease (AD). Accumulating evidence implicates deregulation of Wnt signalling in AD pathology and synapse dysfunction. Wnt signalling plays an important role in synapse formation during development and synapse plasticity and maintenance in the adult brain. Recent studies showed that Dickkopf-3 (DKK3), an abundantly expressed Wnt antagonist, is elevated in the cerebral spinal fluid and accumulates in Amyloid beta (Aβ) plaques in AD patients. However, the role of DKK3 in the brain is mostly unexplored. I examined the function of DKK3 in mature synapses and in AD by performing gain- and loss-of-function studies, and using biochemical, molecular and imaging techniques. I showed that DKK3 is present in neurons, synapses, and astrocytes of the adult hippocampus. DKK3 gain-of-function leads to a decrease in excitatory to inhibitory (E/I) synapse ratio, whereas loss-of-function of DKK3 leads to an increase in E/I synapse ratio in the hippocampus. Exploring the role of DKK3 in E/I synaptic changes after long-term depression (LTD), I discovered that DKK3 secretion is increased and that DKK3 is required for the E/I synapse reorganisation after NMDAR-mediated LTD. These findings reveal a previously unknown role of DKK3 in regulating E/I synapse density and advances our knowledge of E/I synapse balance regulation in the adult hippocampus. Investigating the role of DKK3 in AD, I found that DKK3 secretion is increased in the J20 hippocampus, which exhibits decreased E/I synapse ratio. In addition, I showed that DKK3 accumulates in dystrophic neurites around plaques and promotes plaque expansion, possibly through microglia regulation. My results suggest that DKK3 contributes to AD pathology by controlling plaques growth and may further contribute by affecting E/I synapse imbalance in the hippocampus. In summary, these results demonstrate a novel mechanism, by which deficient Wnt signalling contributes to synapse vulnerability and pathology in AD