TY - JOUR T1 - Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration JF - bioRxiv DO - 10.1101/2020.03.09.976118 SP - 2020.03.09.976118 AU - Juliane Obst AU - Emilie Simon AU - Maria Martin-Estebane AU - Elena Pipi AU - Liana M. Barkwill AU - Yvette Gonzalez-Rivera AU - Fergus Buchanan AU - Alan R. Prescott AU - Dorte Faust AU - Simon Fox AU - Janet Brownlees AU - Debra Taylor AU - V. Hugh Perry AU - Hugh Nuthall AU - Peter J Atkinson AU - Eric Karran AU - C Routledge AU - Diego Gomez-Nicola Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/09/2020.03.09.976118.abstract N2 - The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer’s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases. ER -