Brain catecholaminergic neurons control monocytes deployment to sites of injury and their loss exacerbate cognitive deterioration in an animal model of Alzheimer’s Disease

Abstract

AbstractBackgroundThe CNS constantly monitors the organism’s internal state and orchestrates adaptive responses to perturbation of the body’s homeostasis. Emerging evidence revealed that the brain can also instruct immune responses, which in turn can affect the condition of other organs, including the brain itself.MethodWe used neuronal retrograde‐labelling, flow‐cytometry, mass cytometry, scRNAseq and cognitive tests in animal model of Alzheimer’s disease (5xFAD) to study the relevance of the brain Brain‐Immune axis in the context of Alzheimer’s Disease.ResultsWe found that catecholaminergic neurons are in direct communication with the spleen, the major secondary lymphoid organ of our body. This connection is impaired in an animal model of neurodegeneration (Alzheimer’s Disease ‐ AD), and undermining this communication at early stage of the disease accelerated disease manifestation. We found that monocytes are the most sensitive cell type to noradrenaline released by the splenic nerve and halting neuronal inputs to the spleen impairs monocytes’ migratory capacity. Monocytes are needed to cope with neurodegenerative diseases and acute CNS damage. Upon splenic denervation, we observed reduced number of monocytes in the brain of AD mice and impaired microglia maturation. Upon denervation of the spleen, reduced number of infiltrating monocytes was also observed in a model of retina excitotoxic damage.ConclusionsThese results highlight a novel pathway through which the CNS can control immune function and therefore trigger tissue repairing processes.