When scientists named microglial cells after the Greek word for “glue,” they thought it conveyed all one needed to know about the cells. The cells’ role, it was believed, began and ended with providing connective tissue for neurons, the information carriers of the nervous system.
Research over many years has shown that moniker to be something of an injustice. Today, microglial cells — also known as microglia — are recognized as having multiple functions, with a profound influence on human health. Involved in regulating brain development, maintaining neural networks, and repairing injuries, they’ve also come under scientific scrutiny for their role in Alzheimer’s disease.
In a new study in the Proceedings of the National Academy of Sciences, researchers at Dana-Farber show that in mouse models of Alzheimer’s microglial cells constitute two groups, which have a yin-yang relationship. One group, by far the larger, plays a protective role, gathering and disposing of amyloid β, a peptide that forms the brain plaques found in Alzheimer’s. The second group produces osteopontin, a protein that spurs the inflammation associated with Alzheimer’s and stymies the removal of harmful plaque.
The findings, coupled with experiments showing that blocking osteopontin reduces plaque formation and improves cognition in mouse models, make it a prime target for therapies aimed at halting or reversing Alzheimer’s disease progression. Dana-Farber researchers are exploring partnerships with biotech companies able to create antibody drugs directed against osteopontin.
“Although dysregulation of microglial cells is a major feature of Alzheimer’s disease, the variety of different types of these cells has made it difficult to unravel their contribution to the disease’s development and progression,” says Dana-Farber’s Harvey Cantor, MD, senior author of the study. “In this study, we’ve been able to identify a small subset of microglia that produces osteopontin in animal models of Alzheimer’s, providing a target for future therapies.”
Cantor, an immunologist, hadn’t previously studied Alzheimer’s but was urged to do so by a friend who was concerned about the disease. As he reviewed the medical literature about the genetic irregularities in macroglia, Cantor quickly realized he was in familiar territory.
“The more I looked into it, the more obvious it became that microglia were closely related to macrophages and dendritic cells [two major types of immune cells],” says Cantor, the Baruj Benacerraf professor of Immunology at Harvard Medical School.
When he examined which genes were most upregulated — more active than normal — in microglia cells in Alzheimer’s, the one that leapt out was the gene for osteopontin. Again, Cantor found himself dealing with an old acquaintance. “My lab had cloned the gene years ago because it was a key mediator in the immune response,” he relates. “It sends early-alert signal to the immune system and mobilizes an inflammatory response to stress — including trauma to the brain or stroke.”
(Like “microglia,” the name “osteopontin” is a holdover from a time when the protein’s full repertoire of functions was not known. The “osteo” in “osteopontin” reflects that fact that it was discovered in bone. A more up-to-date name would convey its role in sparking the inflammatory response, Cantor comments.)
“In the context of Alzheimer’s, we found that microglia produce Osteopontin (or OPN) over a long period of time, in response to a form of stress that we have yet to identify,” Cantor explains. “We found that chronic OPN production — by a subtype of microglia that accounts for about 5% of all microglia in the brain — is responsible for both the brain-inflammatory component of Alzheimer’s and the inability of other microglia to collect and eliminate developing plaques.”
Two follow-up experiments by researchers in Cantor’s lab reinforced the potential impact of this discovery on Alzheimer’s treatment.
Yiguo Qiu, PhD, and Xianli Shen, PhD, postdoctoral fellows in the Cantor lab and co-first authors of the new study, found that when they shut down the gene for osteopontin in mouse models, none of the animals developed a severe form of Alzheimer’s. They either didn’t develop the disease at all or developed it in a mild form.
In developing an antibody able to neutralize osteopontin — which would be the basis of a potential drug for patients with Alzheimer’s — researchers confronted a barrier, specifically the blood-brain barrier, a tight mesh of blood vessels and tissues that bars harmful substances from the brain. Qiu and Shen overcame that issue by “decorating” the antibody with peptides — short chains of amino acids — that stick to the cells lining the blood-brain barrier, allowing the antibody to be propelled into the brain.
The Cantor group then worked with Michal Beeri, PhD, of the Icahn School of Medicine at Mount Sinai to analyze brain tissue banked from patients with Alzheimer’s disease. They found that tissue samples with the highest levels of osteopontin-producing microglia were from patients with the greatest cognitive declines and the most advanced degree of Alzheimer’s pathology.
The researchers are optimistic that the antibody they’ve developed will prove superior to current antibody treatments for Alzheimer’s. Current treatments target amyloid β plaques, which are thought to form rather late in the disease, whereas osteopontin, the target of the new approach, is involved much earlier in the disease process. Also, the antibodies currently in use bind not only to plaques but also interact with microglia in ways that activate inflammatory responses that can undercut the therapeutic effect of the antibodies.
“Microglia have long been neglected in neurobiology research in comparison to their more glamorous cousins, the neurons. As a result, they have tended to be lumped together into a single group,” Cantor observes. “Our findings begin to outline the division of labor among different types of microglia. They show that a small subset, by producing osteopontin, play an outsized role in Alzheimer’s. These results may set the stage for a largely new approach to therapy for the disease.