Three recent discoveries by University of Southern California neuroscientist Berislav Zlokovic, M.D., Ph.D., have clarified one of the least-understood elements of Alzheimer’s disease: how the blood-brain barrier becomes compromised and contributes to the disease process.
In healthy individuals, the blood-brain barrier (BBB) is a fine mesh filter that transports only select molecules from the body’s main circulatory system into the brain in a highly controlled manner, protecting the more delicate brain from a variety of dangers, and transports certain molecules back out of the brain as well. Changes to the structural components of the BBB have been known to be a normal consequence of aging for decades, but it also has been known for many years that the BBBs of Alzheimer’s patients allow more harmful particles to cross into the brain than the BBBs of those without the disease do.
Precisely when and how, though, does the BBB become compromised, and does it happen as a prelude to Alzheimer’s or as a cause of it? These are essential questions. Alzheimer’s unfolds as a complex cascade of molecular events—one event leads to another, which leads to another, and so on. The effort to stop it rests on understanding all of the key cascade events in the correct sequence—a monumental challenge requiring a coordinated team effort.
The discoveries by Zlokovic—director of the Zilkha Neurogenetic Institute and professor and chair of the Department of Physiology and Biophysics at the University of Southern California, Keck School of Medicine, Los Angeles, and a member of the Cure Alzheimer’s Fund Research Consortium since 2011—bring us one step closer:
“The brain cannot function in the presence of blood-brain barrier breakdown,” said Zlokovic. “Now we know that not only is Abeta important in Alzheimer’s, but also that this barrier, which is regulating transfer of molecules between the brain and blood, and vice versa blood and brain, can become leaky and dysfunctional and lead to subsequent problems likely contributing to onset and progression of dementia.”
Jeffrey Morby, chairman of Cure Alzheimer’s Fund, added, “We created our Research Consortium in order to spur innovation through the speedy sharing of vital data between top researchers. Dr. Zlokovic’s latest advance with PICALM is a perfect example of what we’ve been able to do, and it brings us that much closer to a cure.”
In a significant discovery, a group of proteins long associated with cancer research has been shown to have an important link to Alzheimer’s disease. Among other implications, this advance could fast-track Alzheimer’s drug development, as there are already relevant therapies in active cancer trials.
The protein family, protein kinase C, also known as PKC, helps cells throughout the body and brain respond to cues from their environment—it is an information processor, or “signal transducer.” Balancing the activities of these proteins so that they are active in just the right proportion is essential for cellular homeostasis—functional balance in all of our cells. In a first-of-its-kind study supported by Cure Alzheimer’s Fund (CAF), Dr. Alexandra Newton, Professor of Pharmacology at the University of California, San Diego (UCSD), was able to show that excessively active PKC is associated with Alzheimer’s, thus identifying PKC as a potential therapeutic target.
Dr. Newton has spent virtually her entire career studying the biochemistry and function of PKC. “Because PKCs can be affected by tumor-promoting molecules, the dogma over the past thirty-plus years has been that overly active PKC drives cancer progression,” explained Newton. But things didn’t add up—clinical trials with drugs to inhibit PKC have not only failed but, in some cases, worsened patient outcomes. To find out whether PKC suppresses or promotes cancer, Newton’s lab turned to the disease for an answer. Recent large-scale sequencing of tumors from thousands of cancer patients has identified hundreds of cancer-associated mutations that occur in PKC. Her lab posed the question: are these mutations activating or inactivating? To her surprise, the cancer mutations turned the protein off. “So having PKC is a good thing,” she said. “It protects against cancer. You take it away, and you give the cancer cell a huge survival advantage.”
When CAF Consortium member Dr. Roberto Malinow, a colleague of Newton’s at UCSD, discovered that mice lacking a certain type of PKC had brain differences relevant to Alzheimer’s, he asked Research Consortium Chairman Dr. Rudy Tanzi to look for genetic mutations in PKC in his genome sequencing of Alzheimer’s families. Dr. Tanzi subsequently found relevant mutations. Dr. Malinow then suggested that Dr. Newton examine how these mutations impact PKC function. “Imagine our excitement,” she said, “when we discovered that this mutant PKC, found in four unrelated Alzheimer’s families, had increased activity—the opposite of what occurs in cancer.”
“It’s becoming apparent,” Newton explained, “that PKC is a modulator that keeps signaling pathways in check so you don’t overly signal. Its activity has to be perfectly balanced. If you don’t have enough or if you have too much, you get pathologies.”
Newton’s study was funded as part of CAF’s ambitious new “Genes to Therapies” (G2T) program. “Cure Alzheimer’s Fund was instrumental,” she said, “both in pointing out the mutations and in funding this study. They have changed the direction of our research.”
She added: “This is just the tip of the iceberg. We’ve only looked at one of Dr. Tanzi’s mutations. There’s so much more to do.”
“Collaboration is one of the founding principles of our innovative consortium,” said CAF Chairman Jeffrey Morby. “This groundbreaking research is yet another example of what can be accomplished when you encourage fluid working relationships between the best scientists in the world.”
Building on its enormously successful “Whole Genome Sequencing” Project, which identified nearly 1,000 new genetic mutations in more than 50 different genes, Cure Alzheimer's Fund has announced a new, even more ambitious multiyear, $50 million plus program titled “Genes to Therapies” (G2T). Simply put, the new project’s goal is to use the most promising recent genetic discoveries to develop drugs that would stop the disease at three separate stages:
“This is indeed a major challenge,” said Research Consortium Chair Dr. Rudy Tanzi, “but I believe we now have the data, the technology and the funding to take it on.” The first step, he explained, will be to prioritize approximately 15 genes that fit key several key criteria:
G2T will be aided significantly by the recent “Alzheimer’s-in-a-dish” breakthrough by Tanzi and Dr. Doo Kim at Massachusetts General Hospital. Using human brain cells generated from induced pluripotent stem (iPS) cells, Dr. Kim was—for the first time—able to create both the amyloid plaque and neurofibrillary tangle pathology of AD in a Petri dish. This technology will enable much cheaper and faster drug testing.
“Having learned much about the pathway that leads to disease, together with the genes responsible,” said Tanzi, “we now can proceed to look for chemical compounds that correct the defects. In other words, we can try to fix what is broken.”
Genes to Therapies (G2T) Steering Committee
To ensure the success of the G2T program, Cure Alzheimer’s Fund is funding a unique research facilitation process—the “infrastructure” for the project. This involves recruiting four researchers with expertise in specific genes and providing them with the specialty mice and reagents they will need to do their Alzheimer’s investigations relative to their particular genes. Unlike most projects, which require six to nine months’ preparation time before any real research begins, our unique approach will save money and, most importantly, time, allowing our researchers to get started right away.
Working as one, our G2T Steering Committee’s ultimate goal is to develop effective drug therapies at three different points in the pathological cascade of the disease to prevent, inhibit and cure Alzheimer’s. Here’s a quick look at each of the players.
Rudy Tanzi, Ph.D., chairman, Cure Alzheimer’s Fund Research Consortium
Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) Tanzi was the pioneering scientist who discovered the linkage between specific genes and Alzheimer’s disease. Today Tanzi leads the Alzheimer’s Genome Project™, a groundbreaking initiative dedicated to finding all the genes associated with Alzheimer’s disease so we can not only repair the damage the disease has caused, but prevent it from ever occurring. Tanzi’s role as chair of the G2T Steering Committee is to coordinate the efforts of the researchers as well as to continue his innovative research on what causes Alzheimer’s disease and how it develops.
Sam Sisodia, Ph.D., Cure Alzheimer’s Fund Research Consortium
Thomas A. Reynolds Sr. Family Professor of Neurosciences, University of Chicago
Director, Center for Molecular Neurobiology
A longtime collaborator of Tanzi’s, Sisodia is a leading expert on the molecular and cell biology of Alzheimer’s disease pathology; he has been at the forefront of learning how the familial Alzheimer’s disease (FAD) genes, including the amyloid precursor protein and the presenilins, function normally and contribute to Alzheimer’s disease pathogenesis. His role on the committee is to help identify other researchers, beyond the Research Consortium, who are more familiar with designated genes. Sisodia was very instrumental in designing and implementing the unique “infrastructure” to facilitate more rapid and cost-effective research program for Genes to Therapies.
Dave Michael Holtzman, M.D., Cure Alzheimer’s Fund Research Consortium
The Andrew B. and Gretchen P. Jones Professor of Neurology and Head of the Department of Neurology, Washington University, St. Louis
Like Sisodia, Dr. Holtzman has a background in biology and has helped to identify the most effective interventions from specific gene functional variants in Alzheimer’s disease. Dr. Holtzman is involved in clinical and research activities at the Washington University Memory and Aging Project and the Alzheimer’s Disease Research Center. He has contributed greatly to our understanding of how anti-amyloid antibodies affect Alzheimer’s pathology and how Abeta is cleared from the brains of Alzheimer’s patients. As a member of the steering committee, he will assist in identifying other researchers with similar skills to investigate how the designated Alzheimer’s genes affect the pathology, and bring his clinical experience to bear in setting priorities for potential drug development.
Steven Wagner, Ph.D., Cure Alzheimer’s Fund Research Consortium Principal Investigator, Department of Neurosciences, School of Medicine, University of California, San Diego
Wagner has an extensive background in biochemistry and drug discovery and has numerous patents to his name. Along with Tanzi, he helped develop the first gamma-secretase inhibitor for Alzheimer’s disease, which later provided the platform for gamma-secretase modulators, which control amyloid production rather than stop it altogether. “If we administer this at the right time to the right populations, it could help to slow down the disease process,” said Wagner. As a member of the steering committee, he will focus on genes that may provide clues for early prevention.
Robert Vassar, Ph.D., Cure Alzheimer’s Fund Research Consortium
Professor of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University
Vassar’s ongoing research focuses on the role of Abeta and the enzyme BACE1 in normal biological processes and in disease mechanisms of relevance to Alzheimer’s disease. As a pioneer in Alzheimer’s research, Bob has made a number of discoveries critical to progress in the field. As a member of the Genes to Therapies Steering Committee, he will help ensure proper attention is paid in the G2T research projects to the more basic aspects of how Alzheimer’s-relevant genes are produced and how they affect the disease pathology.
Wilma Wasco, Ph.D.
Associate Professor of Neurology, Genetics and Aging Research Unit,
Massachusetts General Institute for Neurodegenerative Disease, Harvard Medical School and Massachusetts General Hospital
Wasco was part of an international collaborative effort that identified the familial Alzheimer’s disease-associated presenilin 1 (PS1) and presenilin 2 (PS2) genes. Her research has evolved to focus on understanding the biological role certain AD-linked proteins play in the normal, aging and diseased brain. As research operations manager for the G2T project, Wasco will be responsible for facilitating communication among the various researchers, and managing and maintaining the core facilities and research materials, including specially engineered laboratory mice. She also will develop and maintain a G2T publications resource and provide the operations management necessary for this complex and unique undertaking.
Tim Armour, president and CEO, Cure Alzheimer’s Fund Armour brings an extensive background in nonprofits and fundraising to Cure Alzheimer’s Fund as well as an MBA. from Harvard. Armour joined Cure Alzheimer’s Fund 10 years ago to help lead the charge in the quest for a cure. As the administrator of the steering committee, Armour is responsible for supporting the researchers, developing and securing budgets, and being the liaison between the committee and the Cure Alzheimer’s Fund Board of Directors.
A team led by Cure Alzheimer’s Fund Research Consortium Chair Rudy Tanzi, Ph.D., has, for the first time created ‘Alzheimer’s in a dish’ – a combination of both amyloid and tau pathology in human nerve cells living inside a Petri dish.
In September the journal Nature published a study led by Dr. Tanzi that for the first time induced the creation of both key aspects of Alzheimer’s pathologies – amyloid plaques and tau tangles – in human nerve cells with a known Alzheimer’s gene mutation. These nerve cells had been developed first from human stem cells. “In summary, we have successfully recapitulated Abeta and tau pathology in a single 3-D human neural cell culture system for the first time,” wrote Tanzi and fellow researchers in the magazine. Further, the group reported it was able to inhibit both Abeta and tau. “This is a big deal,” Tanzi says. “It creates a near-ideal lab model of the disease that will help us dramatically accelerate the process of drug testing.
A promising first-in-class drug stimulates the creation of new nerve cells in the brains of Alzheimer's mice and will soon be tested in the brains of human patients, thanks to new research by Dr. Sam Gandy, member of Cure Alzheimer's Fund's Research Consortium, at Mount Sinai School of Medicine in New York.
A new article by Gandy's team just published in the journal Molecular Psychiatry outlines the extraordinary promise of the drug, known as a "mGluR2/3 blocker". Created by the Japanese pharmaceutical firm Taisho and originally studied for depression, the drug acts by stimulating stem cells in the hippocampus to divide and form new nerve cells. What's more, the learning behavior of the Alzheimer's mice being treated with the mGluR2/3 blocker has been sustained at its normal level, in contrast to the steady decline of the mice not being treated.
mGluR2/3 originally caught the attention of Gandy and his team for its possible ability to inhibit production of the toxic protein Abeta42, which is associated with Alzheimer's disease. With funding from Cure Alzheimer's Fund, they conducted a pilot study of the drug's effects on a particular strain of mice. That study turned out such promising results that it has drawn $1 million in funding from the Veterans Administration "MERIT Review" program that supports Gandy's lab at the James J Peters VA Medical Center in the Bronx.
The mGluR2/3 blocker has also been administered to healthy young human subjects, and so far has been shown to be safe. The next step for Gandy's team will be to treat elderly human subjects with the drug to test safety in this population before gearing up to test the drug in Alzheimer's disease. With the focus of mainstream Alzheimer's research turning toward prevention, the mGluR2/3 blocker is one of the few drugs that holds promise for repairing brains already damaged by neurodegenerative disease.
All of these efforts proceed from the international Stem Cell Consortium formed by Gandy in 2012 and funded by Cure Alzheimer's Fund. "It's extraordinary that in such a short time, we have moved from ordinary skin cells to induced pluripotent stem cells in a petri dish, to lab-generated human nerve cells, and now to a drug that could potentially create those cells inside a human brain," said Gandy. "We realize that we are unlikely to have much impact in late-stage Alzheimer's, but we are cautiously hopeful that this drug might arrest Alzheimer's disease at an early stage so that patients can remain functional for more extended periods." Gandy's mGluR2/3 blocker is one of five brain cell regenerating agents currently undergoing testing in labs around the world.
"We are so proud of this development," said Cure Alzheimer's chairman Jeffrey Morby. "Helping incubate cutting edge science that can gain momentum with federal funding -- this is precisely why Cure Alzheimer's Fund exists."
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