Reelin Protein Keeps Popping up in Brains that Resist Aging and Alzheimer’s

Reelin Protein Keeps Popping up in Brains that Resist Aging and Alzheimer’s

A protein naturally produced by certain brain cells has garnered significant attention among Alzheimer’s researchers thanks to a recent study about a man from Colombia. 

Investigators say the protein Reelin, which helps in brain development, plays a crucial role in preserving cognitive function and memory in brains affected by Alzheimer’s disease. Besides Alzheimer’s, Reelin also protects the brain from other diseases of aging. 

In 2023, Reelin became what researchers called a “scientific celebrity” after a new study about a Colombian man who did not develop Alzheimer’s disease in middle age like other members of his extended family. The man was from a large family that had a history of early-onset Alzheimer’s disease due to a rare gene variant known as Paisa.

“They start with cognitive decline in their 40s, and they develop full-blown dementia [in their] late 40s or early 50s,” Dr. Joseph Arboleda-Velasquez of Harvard Medical School and Massachusetts Eye and Ear explained to NPR.

Despite having the same variant as his other family members, the man maintained his cognitive health into his late 60s. Many of his family members died from complications of dementia in their 60s. This man was not diagnosed with dementia until he was in this 70s, and died when he was 74. 

An autopsy showed that his brain had sticky amyloid plaques and tau, two hallmarks of Alzheimer’s disease. Tau are tangled fibers that can impair neurons. The tau tangles, however, were mostly absent from the region of the brain where Alzheimer’s disease typically begins, Dr. Arboleda-Velasquez said.

The researchers took a closer look and found that the man carried a rare variant of the gene that makes the protein Reelin. The mutation in the Reelin gene caused the protein to be more active, which researchers believed helped the man to maintain his cognitive health into his late 60s. Although the researchers were not sure how Reelin helped to protect his brain, they found out that cognitive decline begins when the neurons that produce Reelin declines. 

The discovery about Reelin and its association with Alzheimer’s reverberated among researchers. 

“I think we’re on to something for Alzheimer’s,” Li-Huei Tsai, a professor at MIT and director of the Picower Institute for Learning and Memory, told NPR. After the study on the man from Colombia was published, many researchers “started to get excited about Reelin,” Tsai said. 

Lawrence Tabak, the principal deputy director of the National Institutes of Health (NIH), was then NIH acting director when he heard about the discovery. 

“Sometimes careful study of even just one truly remarkable person can lead the way to fascinating discoveries with far-reaching implications,” Tabak wrote in his blog post about the discovery.

Nearly seven million people in the United States are living with Alzheimer’s, and that number is expected to increase to almost 13 million by 2050, according to the Alzheimer’s Association. In 2021, Alzheimer’s disease was the fifth-leading cause of death among people ages 65 and older. 

As Alzheimer’s progresses, the disease’s symptoms, such as memory loss, poor judgment, and disorientation grow worse and interfere with a person’s ability to perform daily living activities. 

Colombian Family A Major Focus In Alzheimer’s Research

Although recent focus was on the man from Columbia, his extended family members have been involved in scientific research for more than 40 years. Researchers say the man had about 6,000 blood relatives and about 1,200 had the rare Paisa variant. 

The first family members worked in the 1980s with Dr. Francisco Lopera Restrepo, described as a trailblazing neurologist who led the University of Antioquia’s Clinical Neurology Department. 

During this time, researchers discovered that some family members appeared to be protected by the Christchurch variant, an extremely rare version of apolipoprotein4 (APOE4), a gene that scientists believe raises the risk of developing Alzheimer’s disease.

One of the man’s female relatives, who was found to have two copies of the Christchurch variant, was the subject of a 2019 case report. Imaging tests showed the woman had very high levels of amyloid plaque deposits in the brain but did not show Alzheimer’s symptoms. She did not develop mild cognitive impairment until her late 70s, which was about 30 years later than other genetic carriers in the study.

Besides the Christchurch variant, the scientists identified other family members who appeared to be protected by the gene responsible for Reelin. 

Scientists appreciated the family members who participated in various studies, took experimental Alzheimer’s drugs, and even flew to Boston, MA, to take brain scans and other advanced tests.

“These people agreed to participate in research, get their blood drawn, and donate their brain after death,” Dr. Arboleda-Velasquez told NPR. “And they changed the world.”

More Studies Focus On Reelin

Prior to the study on the man from Colombia, Tsai said his team of researchers was already examining the role that Reelin plays in Alzheimer’s disease. In one study published in September 2023, the team analyzed brains of 427 people and found that those who maintained higher cognitive function as they got older tended to have more of the kind of neurons that produce Reelin. 

In July 2024, the team published a detailed analysis of the brain tissues of 48 people who were deceased. Of the total tissue donors, 26 had symptoms of Alzheimer’s and the rest of the people appeared to have normal thinking and memory when they died. 

The brain tissue of a few of the people who were not diagnosed with Alzheimer’s was full of amyloid plaques. Tsai said the team wanted to know, “What’s so special about those individuals?” So, they performed a genetic analysis of the neurons in six different regions of the brain. 

Tsai said what surprised them most was what they found in the entorhinal cortex, the brain region that supports learning and memory and also shows the earliest signs of Alzheimer’s, such as tau tangles and cell death. This is the same brain region that seemed to be protected against tau tangles in the man from Colombia.

Alzheimer’s appeared to kill off the neurons that produce Reelin, resulting in a decrease in Reelin levels, which makes the brain become more vulnerable.  At the very least, the study “confirms the importance of Reelin,” Dr. Arboleda-Velasques said, “which, I have to say, had been overlooked.”

Source Links:

https://www.npr.org/sections/shots-health-news/2024/07/29/g-s1-13519/alzheimers-protein-reelin-brain-aging-amyloid-tau-memory

https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/one-copy-of-genetic-variant-protects-against-early-onset-alzheimers

https://www.masseyeandear.org/news/press-releases/2019/11/researchers-identify-genetic-mutation-tied-to-alzheimers-disease-protection

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