Monocyte-derived microglia and the impact of clonal hematopoiesis on the brain

Prof. Steffen Jung

• A02

Dr. Liran Shlush

• A02

Project Summary

Fate mapping experiments in Cre transgenic mouse models have suggested that microglia originate exclusively from pre-macrophage precursors that arise in the embryonic yolk sac. Conversely, the adult microglia compartment of healthy organisms is assumed to resist seeding by monocyte-derived cells that arise hematopoietic stem cells (HSC). Recently, we however found that selected non-corti cal brain region of healthy aging animals progressively accumulate monocytederived cells. In contrast to earlier reports, these cells adopt morphological and transcriptomic bona fide microglia signatures and become virtually indisti nguishable from yolk sac-derived microglia (YsMg). Interestingly, emerging data obtained from brains of healthy aged individuals support our fi nding and suggest that monocyte-derived microglia (MoMg) can also constitute a substanti al fracti on of the human microglia compartment. Given that MoMg adopt YsMg identity, progressive replacement might not have negative impact but could mean beneficial CNS rejuvenation.
However, due to their HSC derivati on, MoMg are, unlike YsMg, targets of somatic mutations associated with clonal hematopoiesis (CH). CH variant-carrying MoMg could hence, as reported for cardiovascular pathologies, be associated with CNS pathologies of the elderly. Indeed, we established that hematopoietic expression of DNMT^3AR822H, a common CH mutation in humans, renders MoMg to promote in the respective aging animals motor deficits resembling atypical Parkinsonian disorders. Here we will extend our recent work in pre-clinical models to gain mechanistic insights in the link between CH and brain pathologies (Aim 1) and investigate a potential connection between CH and Parkinson-like and other CNS disorders in humans (Aim 2).