Downregulation of Dickkopf-3, a Wnt antagonist elevated in Alzheimer's disease, restores synapse integrity and memory in a disease mouse model.

ABSTRACT

Increasing evidence supports a role for deficient Wnt signaling in Alzheimer's disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPPNL-G-F/NL-G-F mouse AD models, extracellular DKK3 levels are increased and DKK3 accumulates at dystrophic neuronal processes around plaques. Functionally, DKK3 triggers the loss of excitatory synapses through blockade of the Wnt/GSK3ß signaling with a concomitant increase in inhibitory synapses via activation of the Wnt/JNK pathway. In contrast, DKK3 knockdown restores synapse number and memory in hAPP-J20 mice. Collectively, our findings identify DKK3 as a novel driver of synaptic defects and memory impairment in AD.

Alzheimer's disease is the most common form of dementia worldwide. The cognitive decline typically observed in this condition is associated with the weakening and eventually the loss of synapses, the structures that allow neurons to communicate. Increasing evidence points to this deterioration being linked to deficiency in the Wnt signalling pathway, a cascade of molecular events crucial for brain function and development. The DKK protein family helps to tightly regulate the Wnt pathway by dampening its activity. Previous work suggests that DKK proteins could also be connected to Alzheimer's disease. For example, an elevated amount of DKK1 leads to synapse and memory defects in mice, while brain production of DKK1 is increased in individuals with late Alzheimer's. More recent studies show high levels of another DKK protein, DKK3, in Alzheimer's patients. This protein is also present in the harmful amyloid-ß aggregates, named 'plaques', that typically form in the brain in this condition. Despite these findings, how DKK3 participates in synaptic health remains unclear. To address this question, Martin-Flores, Podpolny et al. tracked DKK3 levels in the brains of Alzheimer's patients, revealing that they increase early in the disease. Additional experiments in Alzheimer's mouse models suggested that DKK3 secretion rise before amyloid-ß plaques form, with the protein then accumulating in abnormal neuronal structures present in the surroundings of these toxic deposits. Martin-Flores, Podpolny et al. then examined the impact of DKK3 on the Wnt pathway, and ultimately, on the balance between synapses that control neuronal activity. These experiments showed that elevated DKK3 levels are linked to a loss of synapses which are excitatory, with a concomitant increase in those that are inhibitory. Crucially, reducing DKK3 levels in a mouse model of Alzheimer's restored this synaptic balance and improved memory, highlighting DKK3 as a potential driver of cognitive impairment. Overall, these findings help to refine our understanding of the molecular mechanisms that contribute to synaptic impairment in Alzheimer's disease. They may also be relevant for researchers studying other conditions that involve aberrant activity of the Wnt pathway, such as cancer.