6 August 2011. Immune cells have been shown to play a role in clearing Aβ from the brain, but it's not clear exactly which subset of cells is responsible. Is it the phagocytes already present in the brain—the microglia—or are new cells recruited from the circulatory system? It's hard to tell, because once in the brain, they all look alike. Researchers are trying to pinpoint the key cell group so that they can design targeted therapies to stimulate them to clear Aβ and perhaps ward off Alzheimer's disease. A study in the August 3 Journal of Neuroscience lends new evidence that perivascular macrophages (PVMs)—those phagocytes that line the brain's blood vessels—may be key players.
Previous research suggests that the immune cells responsible for amyloid clearance depend on the chemokine receptor CCR2 to help them find and eat away at amyloid (see ARF related news story on El Khoury et al., 2007). So to figure out which cells depend on CCR2, researchers led by Josef Priller of the Charité Universitätsmedizin Berlin and Marco Prinz of the University of Freiburg, both in Germany, created chimeric animals by irradiating APPswe or APPswe/PS1 transgenic mice and replacing their bone marrow cells with grafted cells from mice that either expressed CCR2 (CCR2+/+) or double mutants that didn't (CCR2-/-). They then looked to see which type became engrafted in the brain.
The team, which also included joint first authors Alexander Mildner and Katrin Kierdorf of the University of Freiberg and Bernhard Schlevogt of Universitätsmedizin Göttingen, also in Germany, showed that circulating CCR2+/+ myeloid cells were the ones that crossed into the parenchyma of APPswe/PS1 mice. Furthermore, they showed that irradiation of the whole body, including the head, was required for them to gain entry. But once there, the engrafted phagocytes didn't seem to chew away at the plaques, as has been reported elsewhere (see ARF related news story on Simard et al., 2006). Instead, the data suggested the bone marrow-derived phagocytes in APPswe mice acted at the perivascular compartment. This falls in line with a previous report suggesting that macrophages in and around the blood vessels may be involved in reducing Aβ in the brain by shuttling it out via the perivascular spaces (see ARF related news story on Hawkes and McLaurin, 2009). "This irradiation paradigm reduces amyloid, not in terms of the plaques, but actually in terms of the overall amyloid in the perivascular compartment, around the vessels," said Priller.
To distinguish between the different macrophage activities that might be responsible for clearing Aβ, the team used different methods of irradiation to control whether circulating cells became engrafted in the brain. Since the researchers found that irradiation of the head was required for circulating myeloid cells to enter the brain, they shielded the skulls of some of the mice from the radiation so that circulating myeloid cells were locked out—they could only go as far as the perivascular space. The method generated chimeric APPswe mice whose perivascular macrophages were either CCR2+/+ or CCR2-/-.
The researchers irradiated the animals at three months old. Seven months later , the APPswe mice with CCR2-/- grafts had significantly more insoluble Aβ in their brains than did CCR2+/+ -grafted mice, which the team took to mean that perivascular macrophages modulate Aβ deposition in the brain's blood vessels in a process that depends on CCR2. Conversely, the team compared aged, unirradiated APPswe CCR2-/- mice with aged APPswe CCR2+/+ and found that clearance of Aβ deposition and the number of immunoreactive cells, as shown by the macrophage/microglia marker Iba-1, was similar in both. The result suggests that brain-resident microglia don't depend on CCR2 for clearance. This finding contrasts with other work suggesting that CCR2-deficient mice have fewer microglia and enhanced parenchymal Aβ plaque deposition (see El Khoury et al., 2007).
Priller said the findings implicate perivascular macrophages, rather than microglia, in Aβ clearance. He said the current paper provides a nice link between results showing that reduction in perivascular macrophages enhances cerebral amyloid angiopathy, or CAA (see Hawkes and McLaurin, 2009), and that CCR2 is needed for Aβ clearance (El Khoury et al., 2007). Researchers led by Joseph El Khoury at Massachusetts General Hospital, Charlestown, contended that CCR2-deficient APPswe mice die early because the microglia no longer function, leading to an increase of Aβ plaques in the brain and early death. But Priller says this new work suggests that, rather than affecting the microglia, the CCR2 deficiency affects the perivascular macrophage clearance. This supports work by Terrence Town at Cedars Sinai Medical Center in Los Angeles, California, who reported that stimulating peripheral macrophages by blocking TGF-β1 signaling cleared Aβ from the brain, including the blood vessels (see ARF related news story).
"This study makes me quite comfortable that peripheral macrophages are adept at removing brain vascular Aβ deposits," said Town, who was not involved with the study. But the disagreement with El Khoury’s data still leaves open the question of whether the microglia play a role in plaque breakdown. "I don't think we have closure on the issue of CCR2 dependency of brain parenchymal plaque clearance, because we now have two datasets that aren't completely congruent, " Town added.
Serge Rivest of Laval University, Quebec, Canada, said it's becoming more accepted in the field that neuroprotection doesn't always correlate with changes in plaque load—that subtle changes, such as in cerebrovascular β amyloid clearance, could confer a neuroprotective effect. However, he would have liked to see more behavioral data on the mice, to show that perivascular clearance of Aβ had a positive effect on the brain. "The paper showed that circulating monocytes can be an extremely powerful approach to the disease," said Rivest. "But we need to find out whether these data translate to clearly physiological relevance in these mice using behavioral tests."—Gwyneth Dickey Zakaib.
Mildner A, Schlevogt B, Kierdorf K, Böttcher C, Erny D, Kummer MP, Quinn M, Brück W, Bechmann I, Heneka MT, Priller J, Prinz M. Distinct and Non-Redundant Roles of Microglia and Myeloid Subsets in Mouse Models of Alzheimer's Disease. J Neurosci. 2011 Aug 3;31(31):11159-11171. Abstract