Posts Tagged ‘Kelly Servick’

Francisco Lopera, a neurologist at the University of Antioquia in Medellin, Colombia, has been painstakingly collecting brains, birth and death records from one sprawling Colombian family to study Alzheimer’s.Credit…Federico Rios Escobar for The New York Times

A woman with lots of beta-amyloid buildup (red) in her brain remained cognitively healthy for decades.

by Kelly Servick

In 2016, a 73-year-old woman from Medellín, Colombia, flew to Boston so researchers could scan her brain, analyze her blood, and pore over her genome. She carried a genetic mutation that had caused many in her family to develop dementia in middle age. But for decades, she had avoided the disease. The researchers now report that another rare mutation—this one in the well-known Alzheimer’s disease risk gene APOE—may have protected her. They can’t prove this mutation alone staved off disease. But the study draws new attention to the possibility of preventing or treating Alzheimer’s by targeting APOE—an idea some researchers say has spent too long on the sidelines.

“This case is very special,” says Yadong Huang, a neuroscientist at the Gladstone Institutes in San Francisco, California, who was not involved with the research. “This may open up a very promising new avenue in both research and therapy.”

APOE, the strongest genetic risk factor for Alzheimer’s, has three common forms. A variant called APOE2 lowers risk of the disease. The most common variant, APOE3, doesn’t influence risk. APOE4 raises risk; roughly half of the people with the disease have at least one copy of this variant.

Researchers have long contemplated targeting APOE with therapies. A team at Cornell University will soon start a clinical trial that infuses the protective APOE2 gene into the cerebrospinal fluid of people with two copies of APOE4.

But mysteries about APOE have kept it from becoming a front-runner among drug targets. “It does so many things that it’s confusing,” says Eric Reiman, a neuroscientist at the Banner Alzheimer’s Institute in Phoenix and a co-author on the new paper. The APOE protein binds and transports fats and is abundant in the brain. And the APOE4 variant seems to encourage the formation of sticky plaques of the protein beta-amyloid, which clog the brain in Alzheimer’s. But powerful amyloid-busting drugs have repeatedly failed to benefit patients in clinical trials. Some researchers saw no reason to try an APOE-targeting therapy that seemed to be “just a poor man’s antiamyloid treatment,” Reiman says.

The Colombian woman’s case suggests other ways APOE could affect Alzheimer’s risk. The woman participated in a study led by researchers at the University of Antioquia in Medellín that has tracked roughly 6000 members of her extended family. About one-fifth of them carried an Alzheimer’s-causing mutation in a gene called presenilin 1; these carriers generally developed dementia in their late 40s. Yet the woman didn’t show the first signs of the disease until her 70s, even though she, too, carried the mutation. “She’s definitely an outlier,” says cell biologist Joseph Arboleda-Velasquez of Harvard Medical school in Boston. (The research team is keeping the woman’s name confidential to protect her privacy.)

In Boston, a positron emission tomography scan of the woman’s brain revealed more amyloid buildup than in any other family member who has been scanned. “It was very striking,” says Yakeel Quiroz, a clinical neuropsychologist at Massachusetts General Hospital and Harvard Medical School. But the team found no signs of major damage to neurons, and minimal buildup of another Alzheimer’s hallmark: the misfolded protein tau. Whatever protection this woman had didn’t depend on keeping the brain amyloid-free. Instead, her case supports the idea that tau has a “critical role … in the clinical manifestations of Alzheimer’s disease,” says Jennifer Yokoyama, a neurogeneticist at the University of California, San Francisco.

Genome sequencing revealed two copies of a rare mutation in the APOE gene, the researchers report this week in Nature Medicine. First discovered in 1987, the mutation, known as Christchurch, occurs in a region separate from those that determine a person’s APOE2, 3, or 4 status. (The woman has the neutral APOE3 variant.) Previous research found that the Christchurch mutation—like the more common protective APOE2 mutation—impairs APOE’s ability to bind to and clear away fats and sometimes leads to cardiovascular disease.

The researchers also found that the mutation prevents APOE from binding strongly to other molecules called heparan sulfate proteoglycans (HSPGs), which coat neurons and other cells “like a carpet,” says Guojun Bu, a neuroscientist at the Mayo Clinic in Jacksonville, Florida, who has studied the interaction between these molecules and APOE.

APOE2 may also impair the protein’s ability to bind HSPGs. But how that could protect against disease isn’t clear. One possible clue: Research by neuroscientist Marc Diamond of the University of Texas Southwestern Medical Center in Dallas and his colleagues suggest the toxic tau protein relies on HSPGs to help it spread between cells. Maybe the less APOE binds to HSPGs, the harder it is for tau to spread.

But, Diamond cautions, “It will require much more study to understand if this relationship exists.” The Christchurch mutation might have protective effects unrelated to HSPGs; it’s also possible that mutations other than Christchurch protected the woman.

If hampering APOE’s normal binding really staved off her Alzheimer’s, future treatments might aim to mimic that effect. An antibody or small molecule could latch onto the APOE protein to interfere with binding, gene editing could change the structure of APOE to imitate the Christchurch variant, or a “gene silencing” approach could reduce production of APOE altogether.

Reiman hopes the new study will rally researchers to pursue treatments related to APOE. He, Quiroz, Arboleda-Velasquez, and other collaborators also posted a preprint on the medRxiv server on 2 November showing that people with two copies of APOE2 have lower Alzheimer’s risk than previously thought—about 99% lower than people with two copies of APOE4. “When it comes to finding a treatment that could have a profound impact on the disease,” Reiman says, “APOE may be among the lowest hanging fruit.”

Patterns of gene expression unite the prairie vole Microtus ochrogaster with other monogamous species, including certain frogs, fish, and birds. YVA MOMATIUK AND JOHN EASTCOTT/MINDEN PICTURES

By Kelly Servick

In the animal world, monogamy has some clear perks. Living in pairs can give animals some stability and certainty in the constant struggle to reproduce and protect their young—which may be why it has evolved independently in various species. Now, an analysis of gene activity within the brains of frogs, rodents, fish, and birds suggests there may be a pattern common to monogamous creatures. Despite very different brain structures and evolutionary histories, these animals all seem to have developed monogamy by turning on and off some of the same sets of genes.

“It is quite surprising,” says Harvard University evolutionary biologist Hopi Hoekstra, who was not involved in the new work. “It suggests that there’s a sort of genomic strategy to becoming monogamous that evolution has repeatedly tapped into.”

Evolutionary biologists have proposed various benefits to so-called social monogamy, where mates pair up for at least a breeding season to care for their young and defend their territory. When potential mates are scarce or widely dispersed, for example, forming a single-pair bond can ensure they get to keep reproducing.

Neuroscientist Hans Hofmann and evolutionary biologist Rebecca Young at the University of Texas in Austin wanted to explore how the regulation of genes in the brain might have changed when a nonmonogamous species evolved to become monogamous. For example, the complex set of genes that underlie the ability to tolerate the presence of another member of one’s species presumably exists in nonmonogamous animals, but might be activated in different patterns to allow prolonged partnerships in monogamous ones.

“We wanted to be bold—and maybe a little bit crazy” in the new experiment, Hofmann says. Instead of doing a relatively straightforward genetic comparison between closely related species on either side of the monogamy divide, he and colleagues wanted to hunt down a gene activity signature associated with monogamy in males across a wide variety of species—frogs, mice, voles, birds, and fish. So in each of these groups, they selected two species, one monogamous and one nonmonogamous.

Rounding up the brains of those animals took an international team and years of effort. Hostile regional authorities and a complicated permitting system confronted the team in Romania as they tried to capture two types of a native songbird. Hofmann donned scuba gear and plunged into Africa’s Lake Tanganyika to chase finger-length cichlid fish into nets. Delicately debraining them while aboard a rocking boat, he says, was a struggle.

Back the lab, the researchers then grouped roughly comparable genes across all 10 species based on similarities in their sequences. For each of these cross-species gene groups, they measured activity based on how much the cells in the brain transcribed the DNA’s proteinmaking instructions into strands of RNA.

Among the monogamous animals, a pattern emerged. The researchers found certain sets of genes were more likely to be “turned up” or “turned down” in those creatures than in the nonmonogamous species. And they ruled out other reasons why these monogamous animals might have similar gene expression patterns, including similar environments or close evolutionary relationships.

Among the genes with increased activity in monogamous species were those involved in neural development, signaling between cells, learning, and memory, the researchers report online today in the Proceedings of the National Academy of Sciences. They speculate that genes that make the brain more adaptable—and better able to remember—might also help animals recognize their mates and find their presence rewarding.

It makes sense that genes involved in brain development and function would underlie a complex behavior like monogamy, says behavioral neuroscientist Claudio Mello of Oregon Health & Science University in Portland. But because the researchers didn’t dissect out specific brain regions and analyze their RNA production independently, they can’t describe the finely tuned patterns of gene expression in areas that are key to reproductive behavior. “It seems to me unlikely that by themselves these genes will be able to ‘explain’ this behavior,” he says.

“The fact that they got any common genes at all is interesting,” adds Lisa Stubbs, a developmental geneticist at the University of Illinois in Urbana. “It is a superb data set and an expert analysis,” she says, “[but] the authors have not actually uncovered many important biological insights into monogamy.”

The study did turn up a curious outlier. Some of the genes with decreased expression in most of the monogamous species showed increased expression in one of them—the poison dart frog Ranitomeya imitator. Young notes that in this species’s evolutionary history, fathers cared for the young before cooperative parenting evolved. As a result, these frogs may have had a different evolutionary starting point than other animals in the study, later tapping into different genes to become monogamous.

Hoekstra, who has studied the genetics of monogamy in mice, sees “a lot of exciting next steps.” There are likely mutations in other regions of DNA that regulate the expression of the genes this study identified. But it will take more work to show a causal relationship between any particular genetic sequence and monogamous behavior.

People also often opt for monogamy, albeit for a complicated set of social and cultural reasons. So, do we share the gene activity signature common to monogamous birds, fish, and frogs? “We don’t know that,” says Hofmann, but “we certainly would speculate that the kind of gene expression patterns … might [show up] in humans as well.”