Norepinephrine induces a samaritan phenotype of microglia in an Alzheimer disease mouse model

Loss of locus ceruleus (LC) neurons, degeneration of noradrenergic projections and decrease of norepinephrine (NE) in projection areas represent an early feature of Alzheimer's disease (AD). To elucidate the effect of NE loss on AD pathology, we evaluated NE effects on microglial functions including cytokine generation, migration and phagocytosis in vitro and in vivo. NE stimulation abolished amyloid beta (Aß) induced microglia chemokine and cytokine secretion, but increased microglial migration and phagocytosis of fibrillar Aß in a concentration dependent manner. Similary, DSP4 induced LC degeneration and NE depletion increased mRNA and protein levels of cytokines and inflammatory enzyme systems in APP transgenic mice. NE depleted APPV717I transgenic mice showed more Aß 1–40 and 1–42 deposits within the hippocampus and frontal cortex compared to APP transgenic mice with an intact NE innervation. Confocal analysis of microglial cells and Aß revealed that the number of colabelled cells was higher in control compared to NE depleted APPV717I transgenic mice, suggesting that NE levels modulate microglial phagocytosis in vivo. These data indicate that early LC degeneration and concomitant decrease of NE concentration in LC projection areas such as the neocortex and hippocampus facilitate the inflammatory reaction of microglial cells in the AD brain. At the same time, loss of NE innervation impairs key microglial functions such as migration and phagocytosis and thus contribute to reduced Aß clearance in AD. Therefore, therapies targeting microglial phagocytosis should be tested under NE depletion.