A protein called Reelin may help protect the brain against aging and Alzheimer's disease : Shots

A growing body of research suggests that a key protein called Reelin may help ward off Alzheimer's disease.

GSO Images/The Image Bank/Getty Images

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GSO Images/The Image Bank/Getty Images

A key protein that helps assemble the brain early in life may also help protect it against Alzheimer's and other diseases of ageing.

Three studies published last year all suggest that the protein Reelin helps maintain thinking and memory in diseased brains, though exactly how it works is unclear. Research also shows that reduced levels of Reelin make neurons more vulnerable.

“There is growing evidence that Reelin acts as a 'protective factor' in the brain.” Tsai Li HuiHe is a professor at MIT and director of the Picower Institute for Learning and Memory.

“We think we've discovered something important for Alzheimer's disease,” Tsai says.

This work has stimulated efforts to develop drugs that enhance or increase the activity of Reelin as a way to prevent cognitive decline.

“You don't have to be a genius to say, 'More Leelin, that's the solution.' Dr. Joseph Arboleda Velazquez Researchers from Harvard Medical School and Massachusetts Eye and Ear Infirmary have developed a tool to make this possible.

A very special brain from Colombia

Leelin will be in 2023. study The story of a Colombian man who was expected to develop Alzheimer's disease in middle age but didn't.

The man, who worked as a mechanic, was part of a large family with an extremely rare genetic mutation. PaisaThis comes from the region around Medellín where the gene was discovered, and families who inherit the mutation are almost certain to develop Alzheimer's disease in middle age.

This PET image shows the brain of a Colombian man whose memory and thinking skills remained intact in his late 60s, despite carrying a rare genetic mutation that almost always leads to Alzheimer's disease in his 40s.

Yakiel T. Quiroz Gaviria and Justin Sanchez/Massachusetts General Hospital

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Yakiel T. Quiroz Gaviria and Justin Sanchez/Massachusetts General Hospital

“Cognitive decline begins in people in their 40s, leading to full-blown dementia. [in their] “They're in their late 40s, early 50s,” Arboleda Velazquez said.

However, despite carrying the variant, the man remained cognitively normal into his late 60s and was not diagnosed with dementia until he was in his 70s.

After his death at age 74, an autopsy revealed that the man's brain was covered in sticky amyloid plaques, a hallmark of Alzheimer's disease.

The scientists also found another sign of Alzheimer's disease: tangles of fibers called tau that can damage nerve cells, but curiously, these tangles were rare in a brain region called the entorhinal cortex, which is involved in memory.

This is important because this area is usually one of the first to be affected by Alzheimer's disease, Arboleda Velásquez says.

Researchers studied the man's genome and discovered something that may explain why his brain was protected.

He had a rare mutation in the gene that makes a protein called Reelin, and studies in mice showed that this mutation enhanced the protein's ability to reduce tau tangles.

Although the study focused on a single individual, it made waves in the brain science community and even caught the attention of Lawrence Tabak, then acting director of the National Institutes of Health.

“Sometimes, the careful study of just one truly extraordinary person can lead to fascinating discoveries that have far-reaching implications,” Tabak says. I have written in his blog post about the discovery.

Leelin becomes reality

After the Colombian man's study was published, many researchers “became interested in Li Lin,” Tsai said.

But Tsai's team has already been studying how the protein might play a role in Alzheimer's disease.

In September 2023, the team Published An analysis of the brains of 427 people found that people who maintained high cognitive function as they aged tended to have a higher number of the types of neurons that produced Reelin.

In July 2024, the group will Published Journal Research Nature This provided further support for the Reelin hypothesis.

The study involved a highly detailed analysis of 48 postmortem brains: 26 were from people who had shown symptoms of Alzheimer's disease, while the rest were from people whose thinking and memory seemed normal at the time of death.

Interestingly, several of the seemingly unaffected people had brains riddled with amyloid plaques.

“We wanted to know, 'What is so special about these people?'” Tsai says.

So the team performed genetic analysis of neurons in six different regions of the brain and found several differences, including a surprising one in the entorhinal cortex, which appears to be protected from tau tangles in Colombian men.

“Neurons in the entorhinal cortex that are most vulnerable to Alzheimer's neurodegeneration share one common feature: they highly express Reelin,” Tsai says.

In other words, Alzheimer's appears to selectively damage the neurons that make Reelin, a protein needed to protect the brain from disease. As a result, levels of Reelin decrease and the brain becomes more vulnerable.

The findings are consistent with what scientists learned from a Colombian man with an Alzheimer's disease-resistant brain: He had a variant of the RELN gene that seems to increase the protein's potency, and thus may have compensated for the Reelin deficiency caused by Alzheimer's disease.

At the very least, the study “confirms the importance of Reelin,” Arboleda Velásquez said. “It has, I have to say, been overlooked.”

Colombian family makes big progress

Lilyn's story may never have come to light without the cooperation of some 1,500 members of a large Colombian family with the paisa gene mutation.

The first members of this family were discovered in the 1980s.Dr. Francisco Lopera RestrepoHe is chairman of the Department of Clinical Neurology at the University of Antioquia. Since then, members have participated in a variety of studies, including testing Alzheimer's drugs.

Along the way, the scientists identified several family members who inherited the paisa gene mutation but remained cognitively healthy well beyond the age at which dementia typically develops.

A very rare version APOE gene It is called Christchurch variantScientists now know that other animals also appear to be protected by the gene that causes Reelin.

These two discoveries were made possible because some of the Colombian family members were repeatedly tested in their home country and even flown to Boston for brain scans and other advanced tests.

“These people agreed to participate in a study, to have their blood taken, and to donate their brains after death,” Arboleda Velásquez says, “and they changed the world.”