For the thousands of people diagnosed each year with a neurodegenerative disease, a sobering fact compounds their suffering: Researchers do not know what causes these diseases, let alone what can be done to treat them in most cases.
Neurodegenerative diseases — including Alzheimer’s, Parkinson’s, and multiple sclerosis — are marked by the progressive loss of brain cells called neurons. Depending on where in the nervous system these losses occur, a variety of cognitive and motor symptoms can ensue. For example, loss of muscle control is characteristic of multiple sclerosis. Cognitive declines and personality changes are associated with Alzheimer’s disease.
Researchers have known for some time that a common feature of many neurodegenerative diseases is the heightened activity of helper cells in the brain called macrophages. Scientists have long assumed that these macrophages are hyperactive because they are responding to damage, maybe even trying to heal it.
New research from investigators at the Sloan Kettering Institute contests the bystander role of macrophages. In a study reported in the journal Nature, they show that populations of macrophages harboring certain mutations in their DNA can lead directly to neurodegeneration in mice. Instead of reacting to damage, these cells may be causing it. The results challenge the conventional thinking and open up potential avenues for the diagnosis and treatment of neurodegenerative diseases.
Overactive Cleaning Crew
The SKI investigators didn’t start out looking to challenge the standard view of neurodegenerative diseases. Rather, they were interested in tracing the activities of a particular population of macrophage precursors called erythro-myeloid progenitors (EMPs). Until about five years ago, people didn’t even know that EMPs existed. These cells are derived from the yolk sac of an embryo. (The yolk sac provides the developing embryo with its first, temporary blood supply.) They colonize the developing organs of a fetus and differentiate into macrophages that live on into adulthood. These macrophages provide support to tissues. For example, they scavenge dead cells and other debris in a process called phagocytosis.
“I like to think of them as a cleaning crew of the tissues,” says Elvira Mass, a postdoctoral fellow in the Frederic Geissmann lab at SKI and the paper’s first author. “They clean the area of dead cells and make the tissue happy.”
They are also important during development, she says. That’s when they help sculpt tissue by pruning away some cells to allow others to come forward.
But these sculptor-cleaners can also go into overdrive and remove things that shouldn’t be taken away. When valuable neurons are discarded, that causes trouble. Macrophages in the brain are called microglia.
“There is a whole literature about microglia and neurodegeneration. In general, it’s thought to be a secondary process,” explains Dr. Geissmann, a professor of immunology at SKI and an investigator with the Ludwig Center at MSK. “Essentially, there is tissue damage, so they get activated to eat it. But what we show in this study is that certain somatic mutations that would cause cancer in other cell types instead cause neurodegeneration when they occur in microglia.”
Link between Cancer and Neurodegeneration
The study’s results help make sense of a curious occurrence in the field of cancer. Many people with a type of cancer called histiocytosis, which arises from mutated macrophages in tissues, eventually develop neurodegenerative symptoms many years later. This finding suggested to Drs. Geissmann and Mass that there might be a link between macrophages in the brain, mutations that cause cancer, and neurodegeneration.
To test this hypothesis, they created genetically engineered mice with a mutated version of a gene called BRAF. This mutation is often found in macrophages from people with histiocytosis. (MSK physician-scientist Omar Abdel-Wahab, who treats people with histiocytosis, is a co-author on the paper and helped identify these mutations.) Investigators engineered these mice so the mutant gene was present only in the EMP cells that come from the yolk sac. When they looked in the brains of these mice after about six months, they found signs of neurodegeneration that looked similar to what you see in people with histiocytosis.
“If you follow the mice long enough, they are all sick,” Dr. Geissmann says. “This single mutation is enough to cause neurodegenerative disease.”
The results reinforce a previous — and surprising — finding from the Geissmann lab. Many macrophages found in tissue come from the embryonic yolk sac, rather than from stem cells in the bone marrow (like other blood cells). The investigators further argue that these yolk-sac-derived macrophages could be the cell of origin in a subset of people with histiocytic diseases, including Erdheim-Chester and Langerhans-cell histiocytosis.
New Treatment Options
An exciting possibility raised by this research is using drugs called BRAF inhibitors to treat neurodegenerative diseases. BRAF inhibitors are currently approved for the treatment of BRAF-mutated cancers. When the researchers fed the mice a BRAF inhibitor in their diet, neurodegeneration was prevented. Because the features of microglia in mice and in people with histiocytosis-linked neurodegeneration are similar, they are hopeful that the same thing may hold true in humans.
Current versions of these drugs do not diffuse into the brain very well, so Dr. Geissmann suggests that improvements to these molecules would need to be made to improve their potential efficacy.
The team has plans to investigate whether other somatic mutations activating microglia can be found in people with neurodegenerative diseases. “If neurodegenerative disease in general is a clonal proliferative disease — in lay terms, a cancer — of macrophages, the payoff could be huge,” he says. “Because then we have both the diagnosis and the treatment potentially.”