PT - JOURNAL ARTICLE AU - Nozie D. Aghaizu AU - Sarah Jolly AU - Satinder K. Samra AU - Bernadett Kalmar AU - Katleen Craessaerts AU - Linda Greensmith AU - Patricia C. Salinas AU - Bart De Strooper AU - Paul J. Whiting TI - Microglial Expression of the Wnt Signaling Modulator <em>DKK2</em> Differs between Human Alzheimer’s Disease Brains and Mouse Neurodegeneration Models AID - 10.1523/ENEURO.0306-22.2022 DP - 2023 Jan 01 TA - eneuro PG - ENEURO.0306-22.2022 VI - 10 IP - 1 4099 - http://www.eneuro.org/content/10/1/ENEURO.0306-22.2022.short 4100 - http://www.eneuro.org/content/10/1/ENEURO.0306-22.2022.full SO - eNeuro2023 Jan 01; 10 AB - Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, 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. The DKK1 homolog DKK2 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 DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2+ 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 microglial DKK2 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 DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.