Norepinephrine Promotes Microglia to Uptake and Degrade Amyloid β Peptide through Upregulation of Mouse Formyl Peptide Receptor 2 and Induction of Insulin-Degrading Enzyme

Abstract

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 ␤ peptide (A␤) deposits through uptake of A␤ or releasing cytotoxic substances and proinflammatory cytokines. Here, we investigated the effect of norepinephrine on A␤ uptake and clearance by murine microglia and explored the underlying mechanisms. We found that murine microglia cell line N9 and primary microglia expressed ␤ 2 adrenergic receptor (AR) but not ␤ 1 and ␤ 3 AR. Norepinephrine and isoproterenol upregulated the expression of A␤ receptor mFPR2, a mouse homolog of human formyl peptide receptor FPR2, through activation of ␤ 2 AR in microglia. Norepinephrine also induced mFPR2 expression in mouse brain. Activation of ␤ 2 AR in microglia promoted A␤ 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 ␤ 2 AR on microglia induced the expression of insulin-degrading enzyme and increased the degradation of A␤ 42 . Mechanistic studies showed that isoproterenol induced mFPR2 expression through ERK1/2-NF-B and p38-NF-B signaling pathways. These findings suggest that noradrenergic innervation from LC is needed to maintain adequate A␤ uptake and clearance by microglia, and norepinephrine is a link between neuron and microglia to orchestrate the host response to A␤ in AD.

Norepinephrine Modulates the Motility of Resting and Activated Microglia via Different Adrenergic Receptors

“…Microglia are also well known phagocytes and sources of cytokines and other proinflammatory mediators (22, 60 -63). Both ATP and NE have been reported to separately modulate these functions (11,19,20,46,64). Interestingly, NE pretreatment prevents the ATP-induced p38 phosphorylation and tumor necrosis factor-␣ (TNF-␣) release by mouse spinal cord microglia (41), suggesting that adrenergic signaling and purinergic signaling might interact at multiple levels.…”

“…First, NE might enhance microglial chemoattraction to the amyloid ␤ peptide (A␤)-containing plaques associated with the disease (19). Second, it promotes the clearance of A␤ plaques by increasing microglial phagocytosis of A␤ and elevating the expression of A␤-degrading enzymes (20). Third, NE treatment prevents the A␤-induced increase in proinflammatory cytokine expression (11,19), and lack of NE exacerbates microgliosis in a mouse model of Alzheimer disease (21).…”

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

“…Furthermore, IDE expression and activity can be regulated by several signaling pathways that have been previously connected with AD development, e.g. estradiol [232], norepinephrin [233], NOTCH [234], ApoE [235], PPARγ [236] or S-nitrosylation [237]. Meta-analysis performed by Zhang et al suggested the association between IDE polymorphism and AD [238].…”

Neuroprotective roles of the P2Y2 receptor

“…Accordingly, we suggest that a major effect of P2Y 2 R upregulation in the CNS is to delay the progression of neurodegeneration that occurs with chronic inflammation. It is known that activated astrocytes and microglia internalize and degrade Aβ [217][218][219][220][221], a mechanism that reduces Aβ toxicity in neurons, which is postulated to cause neuronal death in AD. Recruitment of activated microglia to sites of inflammation enhances the phagocytosis of aggregated Aβ via the F c receptor [222,223].…”