Norepinephrine promotes microglia to uptake and degrade amyloid beta peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme.
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 beta peptide (Abeta) deposits through uptake of Abeta or releasing cytotoxic substances and proinflammatory cytokines. Here, we investigated the effect of norepinephrine on Abeta uptake and clearance by murine microglia and explored the underlying mechanisms. We found that murine microglia cell line N9 and primary microglia expressed beta(2) adrenergic receptor (AR) but not beta(1) and beta(3)AR. Norepinephrine and isoproterenol upregulated the expression of Abeta receptor mFPR2, a mouse homolog of human formyl peptide receptor FPR2, through activation of beta(2)AR in microglia. Norepinephrine also induced mFPR2 expression in mouse brain. Activation of beta(2)AR in microglia promoted Abeta(42) 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 beta(2)AR on microglia induced the expression of insulin-degrading enzyme and increased the degradation of Abeta(42). Mechanistic studies showed that isoproterenol induced mFPR2 expression through ERK1/2-NF-kappaB and p38-NF-kappaB signaling pathways. These findings suggest that noradrenergic innervation from LC is needed to maintain adequate Abeta uptake and clearance by microglia, and norepinephrine is a link between neuron and microglia to orchestrate the host response to Abeta in AD.
Kong
Yan
Y
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, People's Republic of China.
Ruan
Lingfei
L
Qian
Lihua
L
Liu
Xiaolei
X
Le
Yingying
Y
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007339:Insulysin / Q000096:biosynthesis* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology* / Q000502:physiology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; C075222:amyloid beta-protein (1-42); C481578:formyl peptide receptor 2, mouse; D007339:Insulysin; D009638:Norepinephrine
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