Kostylev is the third author in a study published in the Wed., Sept. 4 issue of the journal Neuron. The study fills a missing piece in the quest towards understanding the cause of Alzheimer’s disease. The research, conducted at Yale Medical School in the lab of Dr. Stephen Strittmatter, discovered the important role played by a membrane protein, metabotropic glutamate receptor 5, referred to as mGluR5 in Alzheimer’s patients. For the first time, researchers will now have a target to aim for in treatments to halt or reverse Alzheimer’s. In trials on mice with brain defects similar to those of Alzheimer’s patients, treatments aimed at the membrane protein were able to reverse memory damage.
Alzheimer’s disease currently has no cure. It is the most common variety of dementia, a general term for a severe decline in mental ability. Alzheimer’s is the sixth leading cause of death in the United States and affects roughly a third of people over 85 worldwide. Though people have a higher risk of Alzheimer’s as they age, certain forms of the disease manifest themselves in people as young as 40 or 50. Today 5.4 million people suffer from Alzheimer’s in the U.S., and as both population and lifespan increase, this number is expected to triple to 16 million by 2050.
Before chatting with Kostylve, I met the study’s second author, Adam Kaufman, an M.D./Ph.D. student at Yale Medical School, wearing a yellow propylene lab coat and headphones around his neck. Upon meeting me, he ditched the lab coat, kept the headphones, and proceeds to lead me through three long rooms, connecting doors splayed open. We walk past lab tables and shelves packed closely together, piled with electronics and cardboard boxes. A lab mate, Jacqueline Heiss, has been working on studies using several mice now in a cage—“Those are all going to be euthanized,” she explains. Though she warns him against lifting one, Kaufman does anyway, placing it on the back of his bare hand.
Kaufman describes himself as “the mouse guy,” and over his long career in research has only been bitten “thrice.” To prove my bravery, I also accept the cute rodent that he offers to my own hand.
The mouse is apparently unaware that both its purpose and its life are near their end. It also does not realize that many of its kin were involved in something much larger than themselves, a groundbreaking study that may greatly change the course of Alzheimer’s disease research and treatment. The mouse’s warm belly vibrates on the back of my hand as it takes a few steps in either direction.
“Just don’t show it if you are afraid,” Kaufman says, smiling at the mouse. “Show them calm energy, and they’ll be calm too.”
Dr. Strittmatter’s lab is one of many labs at Yale involved in innovative Alzheimer’s disease research. The research projects, though distinct, are all focused on proteins found in the brain that, when assembled improperly, lead to Alzheimer’s disease.
All brains contain a polypeptide known as amyloid beta, or a-beta. A polypeptide is a chain of amino acids, which are the building blocks of a protein. The polypeptide a-beta is 40 amino acids long. But for reasons still not known, sometimes a brain will have a chain that is three amino acids longer. Adding these amino acids changes the shape of a-beta, which causes the proteins to aggregate and form a plaque that is toxic to neurons, cells of the central nervous system; this plaque, or build-up of a-beta proteins, is a major identifying feature of Alzheimer’s.
But from here, the story gets much more complicated. The role that plaque plays in the development of Alzheimer’s disease is not well understood. Dr. Andrew Miranker, an associate professor of Biophysics and Biochemistry at Yale, explains, “When people talk about plaques, these are not really what’s really killing the cells. They’re really a kind of end product.” Some individuals’ brains that have a large build-up of plaque might not exhibit strong symptoms of Alzheimer’s, whereas others with severe forms of the disease may have brains relatively free of plaque.
This perplexing web of Alzheimer’s is tough to untangle – if not plaque, what causes the disease? Dr. Ya Ha, associate professor of pharmacology, believes the disease begins when the a-beta protein is initially formed. The 43 amino acid sequence of a-beta is formed by cleaving off portions of the larger amyloid precursor protein, known as APP. Mysteriously, the reaction that cleaves off components of APP to form a-beta is hydrolytic, or must be carried out in water, but the process is currently thought to take place in a brain cell’s membrane, which is hydrophobic, or water-repellent. Ha’s lab aims to “create a picture” of this seemingly improbable process that creates a-beta.
Once a-beta is assembled, the next step is to understand the proteins. The labs of Drs. Andrew Miranker and Liz Rhoades, professors of molecular biophysics and biochemistry, have discovered the atomic structure of a segment of toxic a-beta. “It doesn’t look like we thought the plaque would look like,” Miranker notes. “It’s a new protein shape, and it’s a new target where we can design and synthesize small molecules.” The teams are also investigating the ability of a-beta to get across the membrane and damage cells’s mitochondria, the structures responsible for generating most of the cells’s energy—“that’s what makes cells sick,” Miranker adds.
The lure of discovery also draws undergraduates to study these cells. Both Miranker and Rhoades’s labs have positions for undergraduate students, one of whom is Juli Coraor, PC ’16. Though Coraor studies physics, this past summer she was drawn to this research in an untraditional path—using physics to investigate the physical structure of tau protein in the cells of a brain with Alzheimer’s. The composition of tau proteins is not essential to understanding the Strittmatter lab’s discovery, but the protein stabilizes the internal structure of nerve cells and is thought to play a role in the development of Alzheimer’s. She will continue to work at Rhoades’s lab this school year and is continually inspired by the implications of the research. “You’re nowhere near any patients. You’re not working with brains,” she explains, “You’re simply working with these clear liquids in a test tube. To think that that could give us information to understanding Alzheimer’s—and eventually curing Alzheimer’s—is pretty amazing.”
While Miranker and Rhodes study a certain toxic segment of the protein, Strittmatter lab’s discovery came out of a question posed about a process farther down the protein’s chain. If the brains of people with Alzheimer’s contain sick cells, they contain an even larger number of sick synapses, or nerves’ way of communicating with each one another. So, the team asked, what is the mechanism that makes a-beta toxic to neurons and synapses? The Neuron paper helps to illuminate the answer to this question.
The study’s first author, Dr. Ji Won Um, has moved to South Korea. So Adam Kaufman explains the study’s first discovery to me. The Strittmatter lab had previously found that prion proteins, proteins that are improperly folded, and a-beta are both found on the membranes of neurons. The presence of both a-beta and prion proteins activates a messenger within the cell called Fyn, which decreases synapse activity. The Strittmatter lab has determined that the protein mGluR5 activates Fyn. This is the missing puzzle piece that scientists had longed to discover: “I’d say that we are, you know, really excited,” Kostylev, the paper’s third author, said. What’s significant about mGluR5 is that there is an existing drug called MTEP that targets the protein. mGluR5 is found in Fragile X syndrome, a genetic disease that leads to cognitive disability and behavioral challenges. MTEP has been proven to successfully regulate mGluR5 levels in Fragile X patients, and researchers hope it could do the same for Alzheimer’s patients.
At this point, Kostylev, a young man with curly blond hair and a confident smile strides in and claps Kaufman on the back, and then announces he’s going to nap on the sofa. This is how I first meet him. Kostylev feigns sleep for a couple of minutes before jumping into the conversation on their paper.
The two-to-four-year period of experimentation that went into the study unearthed “a little piece of evidence here, a little piece of evidence there,” Kostylev says. Finally, these findings joined to form “a much more coherent piece.”
The mice involved in the study had two different forms of Alzheimer’s and were already showing Alzheimer’s symptoms of memory loss. They were given MTEP to target mGluR5, and their memories were tested again. As he nears announcing the final discovery, Kaufman grows more and more animated. He finally explains triumphantly: “Their memory had returned to baseline levels.”
The mice’s mental recovery marks an amazing and unprecedented result for Alzheimer’s-infected individuals, for which there has previously been no cure. Scientists do not study the disease merely for the prestige of discovery; the research can be very personal. Many of the scientists were drawn to search for a cure for the disease after having seen their own loved ones suffer from Alzheimer’s. Dr. Christopher van Dyck, director of the Alzheimer’s Disease Research Unit and Professor of Psychiatry, Neurology, and Neurobiology, reflects that by the time he was in college, studying cognitive function, he “saw [Alzheimer’s] up-close, in my grandfather.”
The Alzheimer’s Disease Research Unit now approaches a final, important step in their research: human clinical trials. These trials will be necessary to check treatments already given to mice: Kostylev and Kaufman acknowledge that while genetically identical mice kept in lab conditions are relatively simple targets for treatment, humans are much more complicated. The Strittmatter lab often collaborates with Dr. van Dyck and will be working with him when they test the methods of the Neuron study on humans.
Beyond the lab doors, undergraduates are likely to see an upsurge in Alzheimer’s advocacy this year. The Yale Undergraduate Alzheimer’s Disease Initiative, which was established as a club last year, is newly revitalized with aims to increase its actions. Zobia Chunara, PC ’16, the club’s president, says she hopes that the club will to start volunteering with Alzheimer’s patients this year. When she was in high school, Chunara participated in a program that paired her with a woman named Millie living in a nursing home. Millie had Alzheimer’s, and hearing about her life experiences motivated Chunara to do research in the field. Another goal of Chunara’s is to host a symposium this spring to showcase the work of Yale professors, from various fields, whose work relates to Alzheimer’s. In two weeks, on Sept. 29, the club welcomes anyone to participate in the New Haven Walk to End Alzheimer’s.
Efforts such as the New Haven Walk hope to bring awareness and funding to the search for a cure, a goal still many years distant from researchers at Yale and beyond. The Neuron paper filled a crucial missing link by isolating the role of mGluR5 in Alzheimer’s, but scientists need political and economic support. Most of all, they need to continue working. Kaufman is cautiously optimistic, and Kostylev even more so. “I mean, it’s just a protein,” Kostylev muses. But, he adds, “You treat diseases one protein at a time.”