Inspired by a family’s struggle, a scientist helps uncover defense against Alzheimer’s disease

(Press-News.org) Rutgers neuroscientist Peng Jiang was visiting his hometown of Qianshan, a city in China’s Anhui province, when a neighbor came to his parents’ house with a story that would stay with him.

The man’s mother had been diagnosed with Alzheimer’s disease in her early 60s. After nearly a decade of decline, she no longer recognized her own son. One morning, she looked at him and asked gently, “How is your mother doing? Is she well?”

As the neighbor recounted the moment, he broke into tears. He told Jiang that Alzheimer’s runs in his family and that he fears his own children may one day watch him fade the way he watched his mother’s memory vanish.

That conversation, which took place several years ago, became a turning point for Jiang, an associate professor in the Department of Cell Biology and Neuroscience at the School of Arts and Sciences. Already deep into Alzheimer’s research, Jiang returned to his lab with renewed urgency.

“The fact that there is still no effective treatment fuels my determination to pursue new therapeutic ideas,” said Jiang, also a faculty member of the Rutgers Brain Health Institute.

Now, Jiang and his neuroscience colleague Mengmeng Jin, the first author of the study, have made a discovery they said could reshape how scientists think about Alzheimer’s treatment. Their study, published in Nature Neuroscience, identifies a rare gene mutation that appears to protect the brain’s immune cells from the damage typically caused by the disease.

“We believe it's a major advance in the field,” Jiang said. “Rather than looking at mutations that increase risk, we're searching for mutations that can confer resilience.”

The work reflects a shift in Alzheimer’s disease research, Jiang said. Instead of focusing only on removing toxic proteins, scientists may be able to strengthen the brain’s own defense system to keep it resilient and healthy longer.

For Jiang, the science is inseparable from the human impact.

“We’re trying to learn from nature to harness a naturally occurring mutation for therapeutic purposes,” he said.

Individuals with Down syndrome, who carry three copies of chromosome 21, almost universally develop early-onset Alzheimer’s disease due to the accelerated accumulation of toxic proteins in the brain. Yet a small subset of people with Down syndrome shows remarkable resilience – they never develop dementia despite having the same pathological buildup.

This observation motivated the Rutgers team to investigate the biological effects of a rare mutation, CSF2RB A455D, identified in the immune cells of a small number of individuals with Down syndrome. Their research reveals previously unknown functions of this mutation and provides new insights into mechanisms that may influence the risk of neurodegeneration.

They focused on microglia, the brain’s immune cells that act as housekeepers, clearing away waste and protecting neurons. Using stem cell technology, the researchers created human microglia with the mutation and placed them into the brains of mice to develop a chimeric mouse brain model, allowing them to observe how these human cells function in a living brain environment. These mice were then exposed to Alzheimer’s-related proteins.

The results surprised researchers. The microglia with the mutation stayed young and avoided long-term inflammation that usually damages brain cells. The cells were better at cleaning up harmful proteins and protecting nearby neurons.

When researchers placed both mutated and unmutated microglia together in brain environments containing Alzheimer’s-related proteins, the mutated microglia slowly took over. The unmutated microglia became weaker over time, while the mutated ones stayed strong, effectively refreshing the brain’s immune system. This effect showed up not only in cells from people with Down syndrome but in cells from the general population.

“We transplant the cells, then inject pathological proteins,” said Jin, a postdoctoral research fellow. “We observe how the human microglia react.”

The discovery opens the door to new therapeutic strategies, the scientists said. One approach involves transplanting microglia engineered with the protective mutation into patients’ brains. Another could involve using gene therapy to introduce the mutation directly into existing microglia, potentially restoring their ability to defend against Alzheimer’s damage.

Other Rutgers scientists who contributed to the study included: Ziyuan Ma, a doctoral student; Rui Dang, a postdoctoral associate; Haiwei Zhang, a former postdoctoral associate; Rachael Kim, a former undergraduate researcher; and Ava Papetti, a graduate fellow, all in the Department of Cell Biology and Neuroscience. Scientists at the University of California, Irvine, Gladstone Institutes, Florida International University, and Nanjing Medical University in China also contributed to the study.

Explore more of the ways Rutgers research is shaping the future.

 

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