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P2‐294: Norepinephrine promotes microglia to uptake and clearance of amyloid β peptide through upregulation of mFPR2 and induction of neprilysin
Author(s) -
Le Yingying,
Kong Yan,
Ruan Lingfei
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1344
Subject(s) - microglia , neprilysin , western blot , downregulation and upregulation , chemistry , receptor , medicine , endocrinology , norepinephrine , microbiology and biotechnology , biology , inflammation , biochemistry , dopamine , enzyme , gene
Background: 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 b peptide (Ab) deposits through phagocytic activity or releasing cytotoxic substances and pro-inflammatory cytokines. Human G-protein coupled receptor FPR2 and mouse homologue mFPR2 are Ab receptors which mediate the uptake of Ab by microglia. Here we investigated the effect of norepinephrine on Ab uptake and clearance by microglia and explored the underlying mechanisms. Methods: The expressions of mFPR2 and b adrenergic receptor (AR) in microglia were examined by real-time PCR and RT-PCR. mFPR2 expression was inhibited by RNA interference. Ab uptake and degradation by microglia were examined by immunofluorescence confocal microscopy and Western blot. Calcium mobilization was measured with FlexStation II system. MAP kinase and IkBa activation, as well as Ab degrading enzyme neprilysin expression were examined by Western blot. Results: We found that murine microglia cell line N9 and primary microglia expressed b2AR but not b1 and b3AR. Norepinephrine and isoproterenol upregulated the expression and functional activity of mFPR2 through activation of b2AR. Activation of b2AR enhanced Ab42 uptake by microglia. Inhibition of mFPR2 expression by RNA interference abolished isoproterenol induced Ab42 uptake by microglia, suggesting that isoproterenol promote Ab42 uptake by microglia through mFPR2. Furthermore, activation of b2AR on microglia induced the expression of neprilysin and increased the degradation of Ab42. Mechanistic studies showed that the inductive effect of isoproterenol on mFPR2 expression was dependent on ERK1/2-NF-kB and p38-NF-kB signaling pathways. Conclusions: These findings demonstrate that norepinephrine promotes microglia to uptake and clearance of amyloid b peptide through upregulation of mFPR2 and induction of neprilysin, and suggest that noradrenergic innervation from LC is needed to maintain adequate Ab uptake and clearance by microglia, norepinephrine is a link between neuron and microglia to orchestrate the host response to Ab in AD.