Beyond its usual business at synapses, the neurotransmitter norepinephrine (aka noradrenaline) seems to help resident phagocytes clear the amyloid-β (Aβ) peptides that accumulate in the brains of Alzheimer disease patients. New research offers two possible mechanisms for this link between nerve signals and microglia. In this week’s Journal of Neuroscience, scientists in China report that norepinephrine nudges microglia to upregulate an Aβ receptor, and to make more of an enzyme that degrades Aβ once it gets internalized. The findings “provide new information for developing strategies to target microglia in AD, which may help avoid side effects of norepinephrine-based treatment,” lead investigator Yingying Le, Chinese Academy of Sciences, Shanghai, wrote in an e-mail to ARF.

Neurons in the locus ceruleus (LC) make most of the brain’s norepinephrine, and their loss correlates with intensified pathology (Bondareff et al., 1987; Marcyniuk et al., 1986) and dementia (Grudzien et al., 2007; see also Weinshenker, 2008, review) in AD patients and in mouse models of the disease (Heneka et al., 2006; Kalinin et al., 2007). Supplying extra norepinephrine seems to help, at least in mice (Heneka et al., 2002), and recent work suggests how this may be achieved. Earlier this spring, Michael Heneka, University of Bonn, Germany, and colleagues reported that norepinephrine slows amyloid deposition in APP23 transgenic mice by enabling microglia to chew up more Aβ. The present study adds mechanistic meat to this notion and helps rekindle the debate about the role of LC neurons in AD (see below).

Given that human G protein-coupled formyl peptide receptor 2 (FPR2) and its mouse homologue mFPR2 are functional receptors for Aβ (Le et al., 2001; Tiffany et al., 2001; Yazawa et al., 2001), first author Yan Kong and colleagues wondered whether norepinephrine promotes expression of this protein in microglia. They first checked a murine microglial cell line (N9) and saw dose-dependent induction of mFPR2 mRNA after treatment with norepinephrine or isoproterenol, a β-adrenergic (i.e., norepinephrine) receptor agonist. The researchers confirmed the effects in vivo, injecting each compound into the brains of wild-type mice and showing similar mFPR2 upregulation. Furthermore, Kong and colleagues concluded that, specifically, β2-adrenergic receptors mediate norepinephrine’s effect on mFPR2. They concluded this after showing that N9 and primary microglia express the β2 receptor, but not the β1 or β3 homologues, and that pretreatment with the non-selective β-adrenergic receptor antagonist propranolol wipes out norepinephrine’s mFPR2 induction.

By immunofluorescence confocal microscopy using antibodies to Aβ, the Shanghai team demonstrated that isoproterenol-treated mouse microglia, as well as N9 cells, take up more Aβ42 in culture. And in mFPR2-expressing human embryonic kidney cells (HEK293) small-hairpin RNAs that block mFPR2 expression caused the cells to internalize less Aβ42.

Having established that norepinephrine drives up Aβ clearance in part by upregulating an Aβ receptor (mFPR2), the researchers turned their attention toward Aβ-degrading factors, wondering whether they, too, might mediate norepinephrine’s effects in microglia. Kong and colleagues found that isoproterenol increased expression of both neprilysin and insulin-degrading enzyme (IDE) in N9 cells. However, neprilysin was hardly detectable in primary microglia with or without treatment, prompting the researchers to home in on IDE. They cultured isoproterenol-treated or untreated N9 and primary microglial cells in media spiked with Aβ42, and found that the agonist reduced levels of Aβ in both supernatants and cell lysates. Together with the immunofluorescence data, these observations suggested that “activation of β2 adrenergic receptor on microglia promoted Aβ uptake and degradation,” the authors wrote. Furthermore, the researchers showed that isoproterenol drives up mFPR2 expression in microglia by activating the MAP kinases ERK1/2 and p38, as well as the transcription factor NF-κB.

All told, the data “strengthen the view that degeneration of LC neurons and decreased norepinephrine in LC projection areas affects the microglial neurobiology going on there, especially in uptake of Aβ,” Heneka told ARF.

A key question remains, though, and that is whether giving the brain more of the neurotransmitter makes a difference functionally. “Let’s say you add some norepinephrine into the brain of an AD mouse and increase Aβ clearance,” said Ahmad Salehi, Veterans Affairs Palo Alto Health Care System, California. “Does it improve cognition?” This has yet to be addressed in AD models. Salehi and colleagues reported last year that boosting norepinephrine improved contextual memory in a mouse model of Down syndrome even after neurodegeneration and behavioral deficits had set in (Salehi et al., 2009 and ARF related news story). The Shanghai group plan to look more closely at the involvement of mFPR2 in AD, Le told ARF, but additional work will be needed to ascertain any connection between norepinephrine treatment, Aβ clearance, and cognition in humans.

Even if future work was to show that increasing norepinephrine can work wonders in AD transgenic mice, harnessing the neurotransmitter to treat people would be much more challenging. One question is whether the loss of norepinephrine through LC degeneration occurs downstream or upstream of Aβ deposition. “We don’t know at all when degeneration of the LC region starts,” Heneka said. “We just know that in the brains of patients with mild cognitive impairment (MCI), it’s already almost completely gone.”

Salehi envisions two possible situations. In the first, where LC neurons degenerate upstream of Aβ, their loss crimps norepinephrine output, which in turn means less Aβ clearance. In the second, LC neurons degenerate downstream of Aβ deposition. Here, excess Aβ would damage LC terminals in the hippocampus, the neurons release less norepinephrine, and that would exacerbate synaptic failures set in motion by Aβ. Understanding which scenario dominates could make a difference for treatment strategies. In the first case, “we would use neurotrophic factors to increase function and activity of LC neurons,” Salehi said. But if the LC effects are downstream of Aβ, “we would focus on reducing AD pathology in the hippocampus.”

Another complication is the mercurial nature of microglial effects in AD. The prevailing view seems to be that the cells’ Aβ-clearing capabilities help in early stages of AD, whereas their prolonged activation may cause chronic neuroinflammation and ultimately do more harm than good (see ARF related news story). Hence, “in a therapeutic strategy, if you want the microglia to get rid of Aβ by phagocytosis, you may have to deal with a therapeutic window that is no longer open in patients with clinical symptoms, but only long before,” Heneka said.—Esther Landhuis

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References

News Citations

  1. Adrenaline Jolt—Potential Therapeutic Strategy for AD?
  2. Microglia—Medics or Meddlers in Dementia

Paper Citations

  1. . Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord. 1987;1(4):256-62. PubMed.
  2. . Loss of nerve cells from locus coeruleus in Alzheimer's disease is topographically arranged. Neurosci Lett. 1986 Mar 14;64(3):247-52. PubMed.
  3. . Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer's disease. Neurobiol Aging. 2007 Mar;28(3):327-35. PubMed.
  4. . Functional consequences of locus coeruleus degeneration in Alzheimer's disease. Curr Alzheimer Res. 2008 Jun;5(3):342-5. PubMed.
  5. . Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci. 2006 Feb 1;26(5):1343-54. PubMed.
  6. . Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging. 2007 Aug;28(8):1206-14. PubMed.
  7. . Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease. J Neurosci. 2002 Apr 1;22(7):2434-42. PubMed.
  8. . Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. J Neurosci. 2001 Jan 15;21(2):RC123. PubMed.
  9. . Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain. J Biol Chem. 2001 Jun 29;276(26):23645-52. PubMed.
  10. . Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages. FASEB J. 2001 Nov;15(13):2454-62. PubMed.
  11. . Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ra17. PubMed.

Other Citations

  1. APP23

Further Reading

Papers

  1. . Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009 Nov 18;1(7):7ra17. PubMed.
  2. . Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6058-63. PubMed.

Primary Papers

  1. . Norepinephrine promotes microglia to uptake and degrade amyloid beta peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme. J Neurosci. 2010 Sep 1;30(35):11848-57. PubMed.