AbstractWnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression ofDKK1,an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer’s disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. TheDKK1homologDKK2has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis ofDKK2in mouse models of neurodegeneration, and in human AD brain. InAPP/PS1andAPP^NL-G-FAD mouse model brains as well as inSOD1^G93AALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglialDkk2mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARMDkk2⁺microglia preferentially accumulated close to βAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglialDKK2upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM geneDKK2between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.