The immune system generally does a wonderful job at keeping the body pathogen free, but it has its downside. Aberrant immune responses can cause a variety of debilitating and sometimes lethal diseases, such as rheumatoid arthritis and multiple sclerosis. There are also hints that immune defenses may accelerate the pathology of Alzheimer’s disease (AD). Microglia, the mononuclear phagocytes of the brain, produce a variety of neurotoxins and pro-inflammatory cytokines when activated by amyloid beta, the major component of amyloid plaques. But because microglia may also be responsible for removing much of the plaque material, scientists have been grappling with the scavengers’ role in Alzheimer’s. Now, findings by lead author Joseph El Khoury, HMS assistant professor of medicine, and Andrew Luster, HMS professor of medicine, both at Massachusetts General Hospital, indicate that microglia are protective in a mouse model of the disease—at least in the early stages.
El Khoury, Luster, and colleagues reported March 11 in the online Nature Medicine that when microglial migration is impaired, pathology is accelerated and survival is dramatically shortened in a transgenic mouse model of Alzheimer’s. “While the thinking in the past few years was that microglia may be playing a neurotoxic role, our finding indicates that they can also be neuroprotective,” said El Khoury.
Microglia are distributed throughout the normal brain as sentinels. “They are constantly monitoring the brain, and if they sense danger, such as an infectious pathogen or toxic substance, they will either accumulate where this substance is or send out processes to take care of it,” said El Khoury. In fact, scientists have known for some time that microglia gather around amyloid plaques. But in recent years, work from El Khoury’s, Luster’s, and other labs has revealed that amyloid beta elicits the release of monocyte chemotactic protein-1 (MCP-1) from microglia; MCP-1 is a major chemotactic protein that serves as a homing beacon for migrating microglia. It is also elevated in Alzheimer’s brain tissue. These findings suggest that microglia may tread a chemotactic path from the bone marrow and blood vessels into the brain in response to a buildup of amyloid beta. “So we figured one good way to address the role of microglia in the AD brain is to prevent the cells from coming into the brain or accumulating at plaques,” said Luster.
To inhibit microglial migration, the researchers turned to mice that lack Ccr2, the microglial chemokine receptor that binds MCP-1. El Khoury and colleagues crossed Ccr2-negative mice with transgenic mice that produce mutant human amyloid beta precursor protein (APP). The APP animals have some of the pathology found in Alzheimer’s disease, including an age-dependent buildup of amyloid plaques and learning and memory problems.
“What we didn’t expect to see was such a dramatic and early response,” said El Khoury. The first thing the researchers noted was that the Ccr2-negative APP mice began dying at a very young age. By 130 days old, only 15 percent of the animals survived, as opposed to around 70 percent of the APP mice. Those with only one copy of Ccr2 fared slightly better, 40 percent surviving to day 130, suggesting a gene dosage effect.
Despite their poor survival, the Ccr2-negative APP mice do not seem to have an increased ability to produce amyloid beta compared to their chemokine receptor-positive counterparts. Levels of APP and the enzymes that cleave the precursor to yield amyloid beta were the same in all mice. But the Ccr2-negative animals had significantly higher levels of amyloid beta in the brain, as early as 65 days old, indicating that the peptide may not be getting cleared as rapidly as in control animals. In addition, loss of the chemokine receptor correlated with much higher levels of amyloid beta deposits, which, though normally undetectable in APP mice at 65 days old, were abundant in the Ccr2-negative animals.
The results indicate microglia play a crucial role in the very early stages of pathology by keeping the brain free of amyloid beta. In support of this idea, the researchers found that there were very few microglia in the brain of Ccr2-negative APP mice (see figure) compared to controls. Furthermore, by looking at cell surface markers that distinguish migratory from resident brain microglia, El Khoury and colleagues found that the numbers of migrating cells infiltrating the brain are elevated by about eightfold in APP mice. In contrast, the number of migrating microglia in the brain of Ccr2-negative APP mice are no higher than in wild-type animals. “This is a particularly interesting finding because it establishes part of the mechanism through which microglia are accumulating in the AD brain,” said Luster.
Drugs that block CCR2 are currently being tested in humans with chronic inflammatory diseases such as atherosclerosis, rheumatoid arthritis, and multiple sclerosis. “Our study suggests that such agents could increase the risk of Alzheimer’s disease in some susceptible individuals,” Luster cautions, “and this will be important to watch out for as trials of CCR2 blockers go forward.”
All told, the results indicate that migrating microglia play a crucial and early role in a mouse model of Alzheimer’s, and therefore potentially in the human disease. “By showing that microglia have a protective role in helping remove amyloid beta from the brain, our findings suggest that enhancing the accumulation of these cells may be beneficial to patients with early-stage AD,” Luster said.
Though what happens as the disease progresses may be more complex. El Khoury suggested that microglia may become altered if they remain activated for a long time. This switch could lead to the production of pro-inflammatory cytokines and toxins, such as reactive oxygen species, that have been documented by El Khoury and others. A similar fate befalls monocytes in atherosclerotic plaques: they initially gather to remove plaque material, but subsequently become toxic to the cells of the blood vessels.
In addition to El Khoury and Luster, the co-authors on the study include Michelle Toft, Suzanne Hickman, Terry Means, Kinya Terada, and Changiz Geula. El Khoury, who is working on establishing a neuroimmunology lab at the Center for Immunology and Inflammatory Diseases at MGH, plans to continue studying the role of microglia in Alzheimer’s.