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Indeed, deficient Wnt signaling is causally related to increased expression of<jats:italic>DKK1,<\/jats:italic>an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer\u2019s 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. The<jats:italic>DKK1<\/jats:italic>homolog<jats:italic>DKK2<\/jats:italic>has 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 of<jats:italic>DKK2<\/jats:italic>in mouse models of neurodegeneration, and in human AD brain. In<jats:italic>APP\/PS1<\/jats:italic>and<jats:italic>APP<jats:sup>NL-G-F<\/jats:sup><\/jats:italic>AD mouse model brains as well as in<jats:italic>SOD1<jats:sup>G93A<\/jats:sup><\/jats:italic>ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial<jats:italic>Dkk2<\/jats:italic>mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM\/ARM<jats:italic>Dkk2<jats:sup>+<\/jats:sup><\/jats:italic>microglia preferentially accumulated close to \u03b2Amyloid 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 microglial<jats:italic>DKK2<\/jats:italic>upregulation 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 gene<jats:italic>DKK2<\/jats:italic>between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.<\/jats:p>","DOI":"10.1523\/eneuro.0306-22.2022","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T18:50:13Z","timestamp":1672858213000},"page":"ENEURO.0306-22.2022","source":"Crossref","is-referenced-by-count":14,"title":["Microglial Expression of the Wnt Signaling Modulator<i>DKK2<\/i>Differs between Human Alzheimer\u2019s Disease Brains and Mouse Neurodegeneration Models"],"prefix":"10.1523","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6096-1853","authenticated-orcid":false,"given":"Nozie 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