CCR2-Positive Macrophages: White Knights of Phagocytes?

Immune cells in the brain can act like good soldiers in the fight against Alzheimer’s disease, gobbling up Aβ and keeping the disease at bay. Or, they can stir up trouble by releasing harmful inflammatory cytokines. The line between the two is often a fine one, depending on such factors as timing, location, context, and the particular signaling semaphore of the brain. One cell type that is emerging as a consistent hero of the phagocyte world, however, is the class of monocytes that express the chemokine receptor CCR2. A paper in the April 20 Journal of Neuroscience both confirms previous findings that these cells help to clear Aβ from the brains of AD mice, and further characterizes their effects. Researchers led by Serge Rivest at Laval University, Quebec, Canada, used CCR2 knockout mice to show that memory worsens and soluble Aβ goes up in the absence of these phagocytes. Curiously, the greatest Aβ increase occurred in intracellular, oligomeric forms, suggesting that phagocytes somehow might play a role in removing the peptide from cells. Loss of CCR2 also upregulated harmful cytokines in the brain, highlighting the importance of this receptor for controlling inflammation, as well as implying that enhancing CCR2 expression could be therapeutic.

CCR2 characterizes a subclass of monocytes that originates in the bone marrow. These cells circulate through the bloodstream and infiltrate sites of inflammation, where they differentiate into macrophages and clean up debris. CCR2-positive cells enter the brain when summoned by the chemokine CCL2/MCP-1, which is elevated in AD. Rivest and colleagues previously showed that these cells were important for clearing amyloid plaques (see ARF related news story on Simard et al., 2006). Other researchers have also demonstrated the cleanup skills of peripheral macrophages (see ARF related news story on Hawkes and McLaurin, 2009).

Researchers led by Joseph El Khoury at Massachusetts General Hospital, Boston, furthered the story by crossing CCR2 knockouts with Tg2576 AD mice. They found that without CCR2, monocytes could not get into the brain and Aβ levels increased (see ARF related news story on El Khoury et al., 2007). These mice died young, however, before plaque formation, preventing detailed characterization of the progression of the disease.

To get around this limitation, first author Gaëlle Naert and Rivest crossed CCR2 knockouts with a different AD model, APPswe/PS1. This cross produces mice with normal lifespans, which allowed Naert and Rivest to characterize their pathology and behavior from three months to one year old. The CCR2 knockouts displayed worse spatial and contextual memory than the APP/PS1 control mice, and at younger ages. The effect of CCR2 knockout on Aβ was surprising. Plaque load changed little, but young knockouts had higher levels of intracellular oligomeric Aβ, and these levels correlated with their memory problems. Larger oligomeric assemblies, such as nine-mers, and 12-mers, correlated more strongly with learning defects than smaller oligomers did. As the mice aged, extracellular soluble Aβ levels went up as well. To compare intracellular versus extracellular Aβ, the researchers prepared specific protein fractions using a previously published method (see Lesné et al., 2006), and visualized Aβ by Western blot.

The increase in intracellular oligomeric Aβ is intriguing, said Terrence Town at Cedars-Sinai Medical Center, Los Angeles, California, who was not involved in this study. These data dovetail with a recent finding by his group in which knocking out another receptor found on circulating macrophages, CD45, also increased levels of intracellular oligomers (see ARF related news story on Zhu et al., 2011). These studies suggest that circulating macrophages play a role in removing intracellular Aβ, Town said, which is unexpected and novel. The mechanism is still a mystery, Town noted.

Another surprising finding was that, starting at six months of age, the CCR2 knockouts had more microglia crowding around plaques than did AD control mice. These microglia strongly expressed the fractalkine receptor CX3CR1 and are likely to be a compensatory response to the loss of incoming CCR2-positive macrophages, the authors suggest. Because CX3CR1-positive cells are poor phagocytes, however, Aβ plaques remain untouched. In fact, brain microglia expressing the fractalkine receptor can lead to neuronal death (see ARF related news story on Fuhrmann et al., 2010; ARF related news story on Lee et al., 2010), although they seem to help restrain tau phosphorylation (see Bhaskar et al., 2010).

In the CCR2 knockouts, the microglial cells around amyloid plaques also expressed high levels of the immunosuppressive cytokine TGF-β1 at nine and 12 months of age. TGF-β1 is a key regulator of amyloid removal. In a previous study, Town and colleagues blocked TGF-β1 signaling on macrophage-like cells and saw improved clearance of Aβ (see ARF related news story on Town et al., 2008). AD patients have higher levels of TGF-β1 than do healthy people (see ARF related news story on Wyss-Coray et al., 1997). TGF-β1 typically serves to quiet down the immune system and may keep peripheral macrophages out of the brain, Town told ARF, and so its upregulation in AD could represent a maladaptive response. The brain may be trying to dampen inflammation to protect vulnerable neurons, Town suggested, but in the process it bars efficient Aβ phagocytes like CCR2-positive cells from entering to clear plaques. In the CCR2 knockouts made by Rivest and colleagues, Town said, “What seems to be happening is that removing CCR2 somehow upregulates the TGF-β1 signaling pathway in plaque-associated macrophages, and this retards the cells’ ability to clear the amyloid.”

Rivest is interested in the therapeutic potential of CCR2. He noted that levels of this receptor are low in monocytes of AD patients. His group is trying to find out why this is. “If we understand the mechanism, maybe we will understand how to upregulate it in a more natural way to fight against AD,” Rivest told ARF. Rivest is encouraged that the immune profiles he sees in his model mice are similar to those in AD patients, suggesting that these mice are a good model for studying this issue.

Modulating the immune system is always a tricky proposition, the researchers agree, and has to be done carefully. “You can push immune cells toward a beneficial response, but you can also push them to do significant damage,” Town said. “We have to be mindful of that.”—Madolyn Bowman Rogers

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References

News Citations

  1. Calling for Backup: Microglia from Bone Marrow Fight Plaques in AD Mice
  2. CAA Relief? Specialized Macrophages Help Flush Out Vascular Amyloid
  3. Microglia—Medics or Meddlers in Dementia
  4. Immune Phosphatase Underlies Microglia’s Split Personality in AD
  5. Death by Glia?—Chemokine Receptor Nudges Neuron Loss in AD Mice
  6. Paper Alert: Fractalkine Receptor Hits Aβ, Tau, in Opposite Ways
  7. Macrophages Storm Blood-brain Barrier, Clear Plaques—or Do They?
  8. TGF-β1 Linked to Plaque Formation

Paper Citations

  1. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron. 2006 Feb 16;49(4):489-502. PubMed.
  2. Hawkes CA, McLaurin J. Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1261-6. PubMed.
  3. El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007 Apr;13(4):432-8. PubMed.
  4. Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed. RETRACTED
  5. Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Tan J. CD45 Deficiency Drives Amyloid-{beta} Peptide Oligomers and Neuronal Loss in Alzheimer's Disease Mice. J Neurosci. 2011 Jan 1;31(4):1355-1365.
  6. Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, Haass C, Laferla FM, Kretzschmar H, Herms J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci. 2010 Apr;13(4):411-3. PubMed.
  7. Lee S, Varvel NH, Konerth ME, Xu G, Cardona AE, Ransohoff RM, Lamb BT. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am J Pathol. 2010 Nov;177(5):2549-62. PubMed.
  8. Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010 Oct 6;68(1):19-31. PubMed.
  9. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008 Jun;14(6):681-7. PubMed.
  10. Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, Mucke L. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature. 1997 Oct 9;389(6651):603-6. PubMed.

Other Citations

  1. Tg2576 AD mice

External Citations

  1. APPswe/PS1

Further Reading

Primary Papers

  1. Naert G, Rivest S. CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2011 Apr 20;31(16):6208-20. PubMed.

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