Compounds identified that stabilize retromer protein complex, which protects neurons from amyloid-beta
NEW YORK, NY (April 20, 2014) — A team of researchers from Columbia University Medical Center (CUMC), Weill Cornell Medical College, and Brandeis University has devised a wholly new approach to the treatment of Alzheimer's disease involving the so-called retromer protein complex. Retromer plays a vital role in neurons, steering amyloid precursor protein (APP) away from a region of the cell where APP is cleaved, creating the potentially toxic byproduct amyloid-beta, which is thought to contribute to the development of Alzheimer's.
Researchers have identified a new class of compounds—pharmacologic chaperones—that can stabilize the retromer protein complex (the blue and orange structure shows part of the complex). Retromer plays a vital role in keeping amyloid precursor from being cleaved and producing the toxic byproduct amyloid beta, which contributes to the development of Alzheimer's. The study found that when the chaperone named R55 (the multicolored molecule) was added to neurons in cell culture, it bound to and stabilized retromer, increasing retromer levels and lowering amyloid-beta levels. Image credit: Nature Chemical Biology and lab of Scott A. Small, MD/Columbia University Medical Center
Using computer-based virtual screening, the researchers identified a new class of compounds, called pharmacologic chaperones, that can significantly increase retromer levels and decrease amyloid-beta levels in cultured hippocampal neurons, without apparent cell toxicity. The study was published today in the online edition of the journal Nature Chemical Biology.
"Our findings identify a novel class of pharmacologic agents that are designed to treat neurologic disease by targeting a defect in cell biology, rather than a defect in molecular biology,"said Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Director of the Alzheimer's Disease Research Center in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at CUMC, and a senior author of the paper. "This approach may prove to be safer and more effective than conventional treatments for neurologic disease, which typically target single proteins."
In 2005, Dr. Small and his colleagues showed that retromer is deficient in the brains of patients with Alzheimer's disease. In cultured neurons, they showed that reducing retromer levels raised amyloid-beta levels, while increasing retromer levels had the opposite effect. Three years later, he showed that reducing retromer had the same effect in animal models, and that these changes led to Alzheimer's-like symptoms. Retromer abnormalities have also been observed in Parkinson's disease.
In discussions at a scientific meeting, Dr. Small and co-senior authors Gregory A. Petsko, DPhil, Arthur J. Mahon Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute and Director of the Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medical College, and Dagmar Ringe, PhD, Harold and Bernice Davis Professor in the Departments of Biochemistry and Chemistry and in the Rosenstiel Basic Medical Sciences Research Center at Brandeis University, began wondering if there was a way to stabilize retromer (that is, prevent it from degrading) and bolster its function. "The idea that it would be beneficial to protect a protein's structure is one that nature figured out a long time ago,"said Dr. Petsko. "We're just learning how to do that pharmacologically.”
Other researchers had already determined retromer's three-dimensional structure. "Our challenge was to find small molecules—or pharmacologic chaperones—that could bind to retromer's weak point and stabilize the whole protein complex,"said Dr. Ringe.
This was accomplished through computerized virtual, or in silico, screening of known chemical compounds, simulating how the compounds might dock with the retromer protein complex. (In conventional screening, compounds are physically tested to see whether they interact with the intended target, a costlier and lengthier process.) The screening identified 100 potential retromer-stabilizing candidates, 24 of which showed particular promise. Of those, one compound, called R55, was found to significantly increase the stability of retromer when the complex was subjected to heat stress.
The researchers then looked at how R55 affected neurons of the hippocampus, a key brain structure involved in learning and memory. "One concern was that this compound would be toxic,"said Dr. Diego Berman, assistant professor of clinical pathology and cell biology at CUMC and a lead author. "But R55 was found to be relatively non-toxic in mouse neurons in cell culture."
More important, a subsequent experiment showed that the compound significantly increased retromer levels and decreased amyloid-beta levels in cultured neurons taken from healthy mice and from a mouse model of Alzheimer's. The researchers are currently testing the clinical effects of R55 in the actual mouse model.
"The odds that this particular compound will pan out are low, but the paper provides a proof of principle for the efficacy of retromer pharmacologic chaperones,"said Dr. Petsko. "While we're testing R55, we will be developing chemical analogs in the hope of finding compounds that are more effective.”
The paper is titled, "Pharmacological chaperones stabilize retromer to limit APP processing."The other contributors are Vincent J. Mecozzi (Brandeis University), Sabrina Simoes (CUMC), Chris Vetanovetz (CUMC), Mehraj R. Awal (Brandeis University), Vivek M. Patel (CUMC), and Remy T. Schneider (CUMC).
The authors declare no financial or other conflicts of interests.
The study was supported by the grants from the National Institutes of Health (AG025161), the Alzheimer's Association, Developmental Therapeutics Program of the National Cancer Institute, Medkoo Biosciences, the Fidelity Biosciences Research Initiative, the McKnight Endowment for Neuroscience, the Ellison Medical Foundation, and the Gottlieb Family Foundation.
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer's, Parkinson's, and other age-related brain diseases and to discover ways to prevent and cure these diseases. It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center, which was established by an endowment in 1977 to focus on diseases of the nervous system, and with the Departments of Pathology & Cell Biology and of Neurology to allow the seamless integration of genetic analysis, molecular and cellular studies, and clinical investigation to explore all phases of diseases of the nervous system. For more information, visit The Taub Institute at http://www.cumc.columbia.edu/dept/taub/.
Columbia University Medical Center
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.
The Helen and Robert Appel Alzheimer's Disease Research Institute
The Helen and Robert Appel Alzheimer's Disease Research Institute at Weill Cornell Medical College uses a multidisciplinary approach to study the causes of dementia and develop ways to prevent and treat them. Close cooperation between clinicians and basic researchers allows the Appel Institute to take discoveries from bench to bedside and back again, learning from patients as well as from cellular and animal models of disease. Its motto, "No Stone Unturned,"reflects its mission: to do everything possible to rid humanity of the scourge of neurodegenerative disorders. The Appel Institute is part of the Feil Family Brain and Mind Research Institute at Weill Cornell. For more information, visit http://brainandmind.weill.cornell.edu.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork- Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with Houston Methodist. For more information, visit weill.cornell.edu.
Characterized by academic excellence since its founding in 1948, Brandeis University is one of the youngest private research universities in the United States, as well as the only nonsectarian Jewish-sponsored college or university in the country. Brandeis, named for the late Justice Louis Dembitz Brandeis of the U.S. Supreme Court, combines the faculty and resources of a world-class research institution with the intimacy and personal attention of a small liberal arts college. Brandeis is recognized for its distinguished community of scholars and students who are united in the passionate pursuit of knowledge with a steadfast commitment to social justice.