Restoring synapse integrity and memory in Alzheimer’s disease by downregulation of the Wnt antagonist Dickkopf-3

Increasing evidence supports a role of deficient Wnt signaling in Alzheimer’s disease (AD). Recent studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) is elevated in the human AD brain. Here, we investigate the contribution of DKK3 to synapse integrity in the healthy and AD brain. We uncover a novel genetic link between DKK3 gene variants and AD risk. Our findings show that DKK3 protein is increased in different human brain fractions consistent with disease progression. In the hAPP-J20 and hAPPNL-G-F/NL-G-F AD models, DKK3 accumulates at plaques in the brain. Oligomers of amyloid-β enhance the secretion of DKK3 from cultured neurons and DKK3 secretion is also increased in hippocampal slices of hAPP-J20 mice. In addition, gain-of-function experiments revealed that DKK3 decreases the density of excitatory synapses through inhibition of the canonical Wnt/GSK3β pathway but increases inhibitory synapse density through activation of the Wnt/JNK pathway. Our studies demonstrate that in vivo DKK3 downregulation restores synapse number in hAPP-J20 mice. Importantly, DKK3 knockdown improves memory in this AD model. Collectively, our findings identify DKK3 as a novel driver of synapse defects and memory impairment in AD