Microglial expression of the Wnt signalling modulator DKK2 differs between human Alzheimer's disease brains and mouse neurodegeneration models

Abstract

Wnt signalling is crucial for synapse and cognitive function. Indeed, deficient Wnt signalling 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 Alzheimers disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the central nervous system (CNS), which have furthermore been shown to be modulated by Wnt signalling. The DKK1 homologue 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 {beta}Amyloid 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 post-mortem human frontal cortex from individuals diagnosed with AD or pathological ageing. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognised limitations of using mouse models to recapitulate facets of human neurodegenerative disease. Significance statementThe endogenous negative Wnt regulator Dkk2 is significantly upregulated at the mRNA level in microglia of AD mouse models, implying that microglia derived Dkk2 protein may detrimentally contribute to a reduced Wnt signalling tone in the AD brain, a known pathophysiological manifestation. Indeed, recombinant DKK2 prevented Wnt- dependent synapse formation in cultured neurons. However, DKK2 upregulation was not recapitulated in post-mortem human AD brains. The success of neurodegeneration animal models has relied on pathophysiology that for the most part correctly modelled human disease. Increasingly however, limitations to the validity of mouse models to recapitulate human neurodegenerative disease have become apparent, as evidenced by the present study by the difference in microglial DKK2 expression between AD mouse models and human AD brain.