Locus ceruleus (LC) is the main subcortical site of norepinephrine synthesis. In Alzheimer's disease (AD) patients and rodent models, degeneration of LC neurons and reduced levels of norepinephrine in LC projection areas are significantly correlated with the increase in amyloid plaques, neurofibrillary tangles, and severity of dementia. Activated microglia play a pivotal role in the progression of AD by either clearing amyloid β peptide (Aβ) deposits through uptake of Aβ or releasing cytotoxic substances and proinflammatory cytokines. Here, we investigated the effect of norepinephrine on Aβ uptake and clearance by murine microglia and explored the underlying mechanisms. We found that murine microglia cell line N9 and primary microglia expressed β2 adrenergic receptor (AR) but not β1 and β3AR. Norepinephrine and isoproterenol upregulated the expression of Aβ receptor mFPR2, a mouse homolog of human formyl peptide receptor FPR2, through activation of β2AR in microglia. Norepinephrine also induced mFPR2 expression in mouse brain. Activation of β2AR in microglia promoted Aβ42 uptake through upregulation of mFPR2 and enhanced spontaneous cell migration but had no effect on cell migration in response to mFPR2 agonists. Furthermore, activation of β2AR on microglia induced the expression of insulin-degrading enzyme and increased the degradation of Aβ42. Mechanistic studies showed that isoproterenol induced mFPR2 expression through ERK1/2-NF-κB and p38-NF-κB signaling pathways. These findings suggest that noradrenergic innervation from LC is needed to maintain adequate Aβ uptake and clearance by microglia, and norepinephrine is a link between neuron and microglia to orchestrate the host response to Aβ in AD. Copyright © 2010 the authors.