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Osteopontin may play key role in Alzheimer’s disease

The activity of microglial cells, shown here near a neuron, may be a potential target for Alzheimer’s disease treatment. Juan Gaertner / Shutterstock

Millions of people in the U.S. are living with Alzheimer’s disease, a devastating type of dementia, and the number is expected to rise in coming decades. Currently, no available treatments can substantially slow progression of the disease, let alone reverse it.

Abnormal functioning of certain immune cells found in the brain, called microglia, is a feature of Alzheimer’s disease. But the wide variety of microglia, which all have different jobs, has made it difficult to understand whether they play a role in development of the disease.

An NIH-funded research team has been studying a protein called osteopontin, which can be produced by microglia. This protein contributes to inflammation and has been linked to neurologic diseases, including Alzheimer’s disease. In their new study, the team examined the brains of mice engineered to develop Alzheimer’s disease. They tracked osteopontin production by microglia in the brains. Results were published on February 7, 2023, in the Proceedings of the National Academy of Sciences.

The researchers found that only a small subset of microglia in the brain produced osteopontin. These all belonged to a type called CD11c+ microglia. However, only some CD11c+ microglia produced the potentially toxic protein. As Alzheimer’s disease progressed, the amount of osteopontin production in the mouse brains doubled to tripled.

The team next engineered the mice so that their microglia couldn’t produce osteopontin. These mice showed a marked reduction in the build-up of amyloid-beta (Aβ) plaques in the brain—a hallmark of Alzheimer’s disease. Cognitive function in the mice lacking osteopontin also improved by about 50%.

In further work, the researchers found that osteopontin inhibited a pathway by which microglia in the brain normally remove Aβ, leaving Aβ to form harmful plaques. In contrast, CD11c+ microglia that didn’t produce osteopontin helped with the ingestion and breakdown of Aβ, protecting the brain.

To see whether osteopontin may also play a role in Alzheimer’s disease in people, the team examined brain tissue from people with the disease. Compared to people with normal cognitive function, people with Alzheimer’s had on average three times as much osteopontin—and the microglia that produce it—in their brains. Higher levels of osteopontin correlated with greater severity of dementia.

In a proof-of-concept study, the researchers treated mice engineered to develop Alzheimer’s disease with an antibody that blocks osteopontin. After two months of treatment, the Aβ plaques in the mouse brains decreased by more than half.

“Targeting osteopontin production in the brain represents a potential new approach to the treatment of Alzheimer’s disease,” says Dr. Harvey Cantor of Harvard University, who helped lead the study. Before testing this strategy in people, however, more work is needed to identify potential drugs that could cross into the brain and target osteopontin.

—by Sharon Reynolds