Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed A beta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of A beta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated A beta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to A beta plaque sites and impaired microglial A beta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced A beta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.