A protein called Reelin may help protect brains against aging and Alzheimer’s : Shots

A key protein called Reelin may help stave Alzheimer’s disease, according to a growing pagliaccetto of research.

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GSO Images/The Image Bank/Getty Images

A key protein that helps assemble the brain early per mezzo di life also appears to protect the organ from Alzheimer’s and other diseases of aging.

A trio of studies published per mezzo di the past year all suggest that the protein Reelin helps maintain thinking and memory per mezzo di ailing brains, though precisely how it does this remains uncertain. The studies also show that when Reelin levels fall, neurons become more vulnerable.

There’s growing evidence that Reelin acts as a “protective factor” per mezzo di the brain, says -Huei Tsai, a professor at MIT and director of the Picower Institute for Learning and Memory.

“I think we’imperatore acceso to something important for Alzheimer’s,” Tsai says.

The research has inspired efforts to develop a drug that boosts Reelin helps it function better, as a way to stave cognitive decline.

“You don’t have to be a genius to be like, ‘More Reelin, that’s the solution,’” says Dr. Joseph Arboleda-Velasquez of Harvard Medical School and Massachusetts Eye and Ear. “And now we have the tools to do that.”

From Colombia, a very special brain

Reelin became something of a scientific celebrity per mezzo di 2023, thanks to a study of a Colombian man who should have developed Alzheimer’s per mezzo di middle age but didn’t.

The man, who worked as a mechanic, was part of a large family that carries a very rare gene variant known as Paisa, a reference to the schieramento around Medellin where it was discovered. Family members who inherit this variant are all but certain to develop Alzheimer’s per mezzo di middle age.

This PET image shows the brain of a Colombian man whose memory and thinking remained intact per mezzo di his late 60s, even though he carried a rare gene variant that nearly always causes Alzheimer’s per mezzo di a person’s 40s.

Yakeel T. Quiroz-Gaviria and Justin Sanchez/Massachusetts General Hospital

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Yakeel T. Quiroz-Gaviria and Justin Sanchez/Massachusetts General Hospital

“They start with cognitive decline per mezzo di their 40s, and they develop full-blown dementia [in their] late 40s early 50s,” Arboleda-Velasquez says.

But this man, despite having the variant, remained cognitively intact into his late 60s and wasn’t diagnosed with dementia until he was per mezzo di his 70s.

After he died at 74, an autopsy revealed that the man’s brain was riddled with sticky amyloid plaques, a hallmark of Alzheimer’s.

Scientists also found another sign of Alzheimer’s — tangled fibers called tau, which can impair neurons. But oddly, these tangles were mostly absent per mezzo di a brain region called the entorhinal cortex, which is involved per mezzo di memory.

That’s important because this region is usually one of the first to be affected by Alzheimer’s, Arboleda-Velasquez says.

The researchers studied the man’s genome. And they found something that might explain why his brain had been protected.

He carried a rare variant of the gene that makes the protein Reelin. A study per mezzo di mice found that the variant enhances the protein’s ability to tau tangles.

Although the research focused acceso a single person, it reverberated through the world of brain science and even got the attention of the (then) acting director of the National Institutes of Health, Lawrence Tabak.

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

Reelin gets real

After the study of the Colombia man was published, lots of researchers “started to get excited about Reelin,” Tsai says.

Tsai’s team, though, had already been studying the protein’s role per mezzo di Alzheimer’s.

Con September of 2023, the team published an analysis of the brains of 427 people. It found that those who maintained higher cognitive function as they aged tended to have more of a kind of neuron that produces Reelin.

Con July of 2024, the group published a study per mezzo di the journal Nature that provided more support for the Reelin hypothesis.

The study included a highly detailed analysis of post-mortem brains from 48 people. Twenty-six brains came from people who had shown symptoms of Alzheimer’s. The rest came from people who appeared to have normal thinking and memory when they died.

Interestingly, a few of these apparently unaffected people had brains that were full of amyloid plaques.

“We wanted to know, ‘What’s so special about those individuals?’” Tsai says.

So the team did a genetic analysis of the neurons per mezzo di six different brain regions. They found several differences, including a surprising one per mezzo di the entorhinal cortex, the same region that appeared to be protected against tau tangles per mezzo di the man from Colombia.

“The neurons that are most vulnerable to Alzheimer’s neurodegeneration per mezzo di the entorhinal cortex, they share one feature,” Tsai says: “They highly express Reelin.”

Con other words, Alzheimer’s appears to be selectively damaging the neurons that make Reelin, the protein needed to protect the brain from disease. As a result, Reelin levels decline and the brain becomes more vulnerable.

The finding dovetails with what scientists learned from the Colombian man whose brain defied Alzheimer’s. He had carried a variant of the RELN gene that seemed to make the protein more potent. So that might have offset any Reelin deficiency caused by Alzheimer’s.

At the very least, the study “confirms the importance of Reelin,” Arboleda-Velasques says, “which, I have to say, had been overlooked.”

A breakthrough made thanks to a Colombian family

The Reelin story might never have emerged without the cooperation of about 1,500 members of an extended Colombian family that carries the Paisa gene variant.

The first members of that family were identified per mezzo di the 1980s byDr. Francisco Lopera Restrepo, head of the University of Antioquia’s Clinical Neurology Department. Since then, members have taken part per mezzo di a range of studies, including trials of experimental Alzheimer’s drugs.

Along the way, scientists have identified a handful of family members who inherited the Paisa gene variant but have remained cognitively healthy well beyond the age when dementia usually sets per mezzo di.

Some appear to be protected by an extremely rare version of the APOE gene called the Christchurch variant. Now scientists know that others seem to be protected by the gene responsible for Reelin.

Both of those discoveries were possible because some members of the Colombian family have been examined repeatedly per mezzo di their own country, and even flown to Boston for brain scans and other advanced tests.

“These people agreed to participate per mezzo di research, get their blood drawn, and donate their brain after death,” Arboleda-Velasquez says. “And they changed the world.”