Preventing Immune Response Shows Promise for Alzheimer’s, Other Disorders

Preventing Immune Response Shows Promise for Alzheimer’s, Other Disorders

Researchers believe that processes that can be used to control immune reactions toward a virus may also be used to prevent neurodegeneration in conditions such as Alzheimer’s disease.

To achieve this, researchers blocked the protein PLSCR1 in the brain — a move that prevented immune cells called microglia from attacking and killing neurons.

The study, “Phosphatidylserine exposure controls viral innate immune responses by microglia,” was published in the journal Neuron.

The research team at the Salk Institute for Biological Studies in La Jolla, California, was not focusing on neurodegeneration when they made the discovery. Instead, they wanted to better understand immune reactions to viruses that deliver gene therapies.

Viruses that are used to deliver gene therapies have been modified so they are unable to multiply and cause disease. Still, their presence alters the immune system, which may launch an attack that may itself be harmful — particularly if the gene therapy-delivering virus is used in the brain. Such reactions, therefore, limit the possibility of using gene therapy to address various disease conditions.

“Normally, the immune system will quickly recognize and act upon potential threats such as virally infected cells,” Axel Nimmerjahn, assistant professor at Salk’s Waitt Advanced Biophotonics Center and the paper’s senior author, said in a press release.

“But in targeting PLSCR1, we’ve effectively shielded infected cells from immune attack and increased gene expression from an engineered virus from a few days or weeks to at least six months, creating the potential for much longer-lasting therapies.”

In an effort to learn about the brain’s immune processes, the research team observed the reactions unleashed after injecting a modified virus into the brains of mice. They noted that as the virus entered individual cells, the cells started displaying molecules on their surfaces that flagged the presence of the virus.

The labels, it turned out, were a signal to microglia to stop and assess the situation. While microglia are capable of killing virus-infected cells, this is not always the optimal way of move ahead. Killing the cells may prevent the infection from spreading farther, but it may also damage brain areas that have a very limited capacity to regenerate.

To understand which signals were involved in making these difficult solutions, the research team employed a simple yet labor-intensive approach. They started manipulating the levels of proteins that they knew were involved in cell-to-cell communications and observed the effects.

After removing PLSCR1 (phospholipid scramblase 1), the effects were difficult to miss. When the factor was absent, microglia left virus-containing cells alone, and much fewer inflammatory factors were produced.

“When we saw how much inhibiting PLSCR1 reduced the inflammatory response, we immediately wondered if this mechanism could apply more broadly, not just to virus infection of the brain, but to other types of infections or even autoimmune diseases,” said Yusuf Tufail, a former Salk postdoctoral fellow and first author of the paper.

The effects were not only pronounced but also durable, with effects continuing for up to six months. None of the other investigated molecules had such a large impact.

Importantly, microglia are known to accumulate around amyloid plaques in Alzheimer’s patients.

“Given how complex the immune response is, and how many genes are regulated up or down in response to infection, it was amazing to find a single protein that controls so many pathways,” Nimmerjahn said.

“Imagine a small molecule inhibitor that a patient could take to curb excessive inflammation. This could have a hugely beneficial effect on many disease outcomes,” he added.

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