Contributions of IL34 Signaling to Microglial Function and Alzheimer’s Pathology in Mice

A loss-of-function mutation in a gene that encodes an important signaling molecule (interleukin 34; IL34) for neuronal communication with the brain-resident immune cells, microglia, has recently been identified in Alzheimer’s disease (AD). To study the role of IL34 in microglial function and AD-like pathology, we created a novel mouse model that combines a partial mutation in IL34 with five familial mutations that confer risk for Alzheimer’s disease (5XFAD). We found that male mice harboring one copy of the IL34 mutation had less plaque accumulation and smaller plaques than control 5XFAD mice but had exacerbated cognitive issues with anxiety and locomotor tasks. We also found that overexpression of IL34 in the hippocampus at eight months increased the number of microglia in the hippocampus but was not effective at rescuing anxiety changes. IL34 overexpression was partially effective at restoring the motor abnormalities that are present in 5XFAD mice. Our results suggest that mutations in the IL34 gene in Alzheimer’s disease modify the accumulation of amyloid plaques in the brain and impact cognitive outcomes and that IL34 overexpression in the brain may be protective. In a set of follow-up experiments, we plan to overexpress IL34 in another brain region, the lateral septum, where we observed the highest density of amyloid plaques in our 5XFAD mutant mice. We hypothesize that this intervention will more effectively prevent the anxiety and locomotor changes we see in our mice and establish IL34 as a potential therapeutic target for the treatment of Alzheimer’s disease.