2015 Turken Research Award Symposium
Ms. Beth Devermont, President and Director of the Sam and Ida Turken Charitable Foundation, is the daughter of Phyllis Turken Shamberg who began donating funds to Alzheimer’s research on behalf of the Sam and Ida Turken Charitable Foundation in the 1980's. In early 90’s, Mrs. Shamberg initiated her first gift to UCLA, known as the “Turken Research Award”. Each year, Ms. Devermont continues her mother’s legacy by providing an annual gift to support early career researchers who are studying Alzheimer’s disease (AD). Over the years, the Turken Research Award has funded twenty-four innovative AD projects including human brain mapping research, PET imaging in early diagnosis, study of cell death mechanisms, and research on dementia genetics.
This year, we are delighted to announce that the Turken Review Committee has selected Dr. Florence Roussotte, Ph.D., to become the 25th Turken Research Award recipient. Dr. Roussotte received her Bachelor’s and Doctoral degrees in Neuroscience from UCLA, in 2007 and 2011. She conducted her postdoctoral research in the laboratory of Dr. Paul Thompson, Ph.D., himself the recipient of the Turken Research Award in 2003. To enhance the breadth of her multidisciplinary research, Dr. Roussotte also obtained an Associate of Science degree in Mathematics from Los Angeles City College in 2012.
The day began with a visit of Ms. Devermont and her guests to the laboratory of Dr. Gal Bitan, Ph.D. in the Neuroscience Research Building. Dr. Bitan, who received the Turken Award in 2005, discussed with the donor and her guests the development of a novel experimental drug in his laboratory (see A New Experimental Drug Targets the Two Rogue Proteins in Alzheimer’s Disease). The drug stops the formation of the toxic protein aggregates – amyloid plaques and neurofibrillary tangles – that form in the brain of people with Alzheimer’s disease. Members of Dr. Bitan’s research group also showed Ms. Devermont and her guests the latest developments in their different projects.
“I was impressed by the depth of questions Beth and her friends asked,” said Dr. Bitan. “They clearly are very interested in the ongoing research at the UCLA-Easton Center and want to stay involved and support what we do. I am very grateful for their support and for the Turken Award that has helped me and so many of my colleagues jump start our careers when we were in the vulnerable stage of starting our research programs.” He added.
As the day continued, Drs. Edmond Teng, M.D., Ph.D., Sally Frautschy, Ph.D., Lin Jiang, Ph.D., and Pete Heinzelman, Ph.D., each gave a talk on the topic of their own research studies. 30 posters were on view during the symposium’s poster session that allowed intense discussion and interactions among the researchers and the trainees in the Center. The event concluded with a luncheon and a scientific presentation by Dr. Roussotte.
Dr. Edmond Teng’s talk focused on the potential mechanisms by which docosahexanoic acid (DHA), one of the primary components of fish oil, might help prevent Alzheimer’s disease. While DHA has a number of properties that are beneficial for brain health, his work suggests that DHA may also modulate the aggregation of beta-amyloid, one of the main pathogenic proteins that accumulate in AD. His group found that when a transgenic rat model of AD was fed a DHA-supplemented diet, these animals had lower levels of neurotoxic beta-amyloid aggregates than control animals that were fed a DHA-depleted diet. These findings raise the possibility that DHA may either directly interfere with the formation of toxic β-amyloid aggregates or stimulate the brain’s immune system to break them up.
Dr. Sally Frautschy discussed complement activation in Alzheimer’s disease, a type of neuroinflammation causing brain damage. Although essential to our immune system, complement actyivation can be triggered by two proteins known to contribute to AD: tau and beta-amyloid (Aβ). Aβ binding of C1q, the main instigator of the complement pathway mediated Aβ toxicity. However, C1q itself showed divergent effects on Aβ, tau and memory, exacerbating memory loss, increasing tau yet reducing Aβ. Understanding how C1q differentially affects tau and Aβ may facilitate combination approaches that clear amyloid without increasing tau by limiting complement activation.
Dr. Lin Jiang presented his research on “Modulate Protein Aggregation in Alzheimer’s Disease by Structure-Based Design”. His laboratory used an integrated approach, combining computational methods and identification of amyloid structures, to target protein aggregation of amyloid beta (Aβ), which has been linked to Alzheimer’s disease. He developed a series of lead compounds, which can modulate the process of Aβ aggregation and inhibit Aβ cytotoxicity in cell-based assays. This structure-based amyloid inhibitor offers a new potential treatment for AD.
Dr. Pete Heinzelman highlighted the "Windows Into the Brain" research initiative, an effort that is enabling high fidelity characterization of the proteins and nucleic acids that comprise bloodborne brain exosomes, nanometer-sized vesicles secreted by brain neurons that are accessible via standard blood draws. This research program holds exciting potential to lead to the discovery of new AD drug targets, noninvasive AD diagnostics, and patient blood tests that allow prediction of AD therapeutic efficacy.
Dr. Florence Roussotte, the 2015 Turken Research Awardee concluded the symposium by presenting “Neuroimaging and Genetic Risk for Dementia.”
The symposium was a great and resounding success. The event allowed the UCLA-Easton Center faculty, trainees and collaborators to share data and ideas for future collaborations.
Please join the UCLA-Easton Center, the Sam and Ida Turken Charitable Foundation, and the Alzheimer’s Association, California Southland Chapter, in congratulating Dr. Florence Roussotte as the 2015 recipient of the Turken Research Award!
A New Experimental Drug Targets the Two Rogue Proteins in Alzheimer's Disease
Dr. Gal Bitan is an Associate Professor in the Neurology Department, David Geffen School of Medicine at UCLA. A native of Israel, Dr. Bitan did his undergraduate and graduate studies at the Hebrew University of Jerusalem, where he first discovered his passion for making novel drugs for cureless diseases.
During his postdoctoral studies at Harvard Medical School/Brigham and Women’s Hospital, Dr. Bitan focused his research on the phenomenon of “abnormal protein aggregation”. When proteins stick to each other and clump together, they form toxic aggregates. These toxic aggregates cause devastating diseases, such as Alzheimer's, Parkinson's, Huntington's, ALS (Lou Gehrig’s disease), systemic amyloidosis, and about 30 others.
The brain of a person who died from Alzheimer's disease is severely shrunk due to massive death of neurons in the hippocampus – the area responsible for short-term memory, and the cerebral cortex – the large region in the front and top of the brain where our thoughts and emotions are processed and our long-term memories are stored. Even before the neurons die, in the early stages of Alzheimer's disease, the connections between neurons, the synapses, are interrupted. This interruption disrupts memory formation and general thought processes, and causes the confusion and emotional disturbance that characterize early Alzheimer’s.
The cause for the brain's deterioration is the abnormal aggregation of two different brain proteins, called amyloid-beta (Abeta) and tau. Abeta is the “instigator” that interferes with the connection between neurons and subsequently kills them, whereas tau is the “propagator” whose clumping occurs later, but is a major contributor to massive killing of neurons. Sadly, several clinical trials attempting to combat these vicious protein aggregates have failed in recent years. Perhaps a major reason for the failures was that the tested drugs targeted either Abeta or tau, but not both. On the other hand, recent development in imaging of the amyloid and tau in the brain using PET scans suggests that now is an opportune time for developing and testing new drugs.
Figure 1.Dr. Bitan’s research program aims at developing novel drugs for the diseases caused by abnormal protein aggregation. The program includes a network of over 30 laboratories around the world working in collaboration on the drug-development program led by Dr. Bitan (for more details, see www.btdd.org). The result of these combined efforts is an experimental drug called CLR01, which dissolves existing toxic protein clumps and prevents formation of new clumps.
CLR01 has been found to be effective against many different toxic protein aggregates and showed significant improvement in a number of scientific models of different diseases. Dr. Bitan worked with members of the Easton Center, including Dr. Sally Frautschy and Dr. Edmond Teng to demonstrate that CLR01 cleared the brain of mice and rats, which had been genetically engineered to develop Alzheimer's disease, from the toxic aggregates of both Abeta and tau (See Figure 1) CLR01 is unique in its ability to reduce both types of pathological proteins simultaneously.
In addition to these exciting results, CLR01 also has shown beneficial therapeutic effects in scientific models of Parkinson’s disease and systemic amyloidosis. Importantly, in all of these experiments, the experimental drug showed high safety and no side effects. Dr. Bitan and his collaborators are seeking funding that will allow them to initiate human clinical trials.
Dr. Bitan has published over 90 articles and book chapters in the scientific literature. He has served as a reviewer for more than 80 scientific national and international journals and funding agencies. He serves on the editorial boards of Scientific Reports and Journal of Biological Chemistry, and the scientific advisory boards of the American Federation for Aging Research and Give to Cure. He obtained research funding from multiple sources, including the National Institutes of Health, Alzheimer's Association, Cure Alzheimer’s Fund, United States–Israel Binational Science Foundation, Michael J. Fox Foundation, Parkinson’s Alliance, CurePSP, and private foundations supporting ALS research. He also received the Turken Award for Alzheimer's Research.
Brain-Body Connections and Alzheimer's Disease
The Mary S. Easton Center for Alzheimer’s Disease Research is committed to finding new treatments for Alzheimer’s disease (AD) and to developing technologies to advance this goal. The latest AD research suggests that AD may have systemic causes or that disorders in other organs contribute to progressive dementia and brain atrophy.
To enhance a systems-level analysis of AD, the Easton Center has recently recruited Alexei Kurakin, M.S., Ph.D., who brings with him over 15 years of multidisciplinary expertise in experimental and theoretical research in biophysics, biochemistry, molecular and cell biology, bioinformatics, systems biology, cancer, and neurodegeneration. Prior to joining the Easton Center, Dr. Kurakin held research positions at the Copenhagen University, the University of Madison-Wisconsin, the Buck Institute, and Harvard Medical School. The unifying theme and overarching focus of his research are the organization, structure, and dynamics of complex networks, such as amino acid networks in proteins, signaling and metabolic networks in cells, and intercellular networks in tissues and microbial communities. Using bioinformatics and artificial intelligence methods, Dr. Kurakin develops novel algorithms that allow for the rapid tracking down, extraction, and synthesis of relevant data and information obtained by disparate disciplines and technology platforms that study biochemical-, molecular-, cellular-, and organism-level processes and networks but which rarely communicate with one another due to interdisciplinary barriers. The extracted data and information are then used to generate comprehensive integrative models that describe the structure and dynamics of the interconnected networks of organs, tissues, cells, and molecules that constitute the organism.
It is useful and revealing to view the human organism as a network of networks, one network nested inside another. On one level, networks of coordinately interacting molecules constitute cells, on the next level, networks of interacting cells form tissues, whereas networks of interacting tissues and organs constitute the organism. All different levels in this hierarchy of networks are interconnected and interdependent. All levels and networks continuously influence and shape one another via a system of mutual controls to keep the organism as a whole in a state of dynamic harmony and balance in the face of external and internal changes, stresses, and challenges. A cell, for example, shapes and coordinates the behavior of its molecules while being shaped both by its molecular constituents and by a network of neighboring cells that constitute its host tissue. In a similar manner, coordinately interacting individuals form businesses and organizations, whereas networks of interacting organizations form industries, and industries form national economies, with all different levels and networks being interconnected into the World System, which they try to keep in a state of dynamic harmony and balance in the face of external and internal challenges and stresses.
In complex multi-level networks, such as the World System or the human organism, a relatively small yet significant number of key nodes – individuals, organizations, and nations; or molecules, cells, and organs, respectively – coordinate and manage large domains of collective activities, by forming stable yet changing relationships and alliances. Consequently, when key managing nodes and/or control relationships malfunction, are unbalanced, or disrupted, large network domains (e.g., organizations, industries, nations; or tissues, organs) suffer a decline in their performance, followed by progressive degeneration, and, if not corrected in time, eventual collapse and disintegration. Notably, in large networked systems, manifestations of a problem can be potentially far removed from their origins. As an example, a chronic low-grade gut inflammation fueled by food allergies or toxins can increase gut permeability, leading to a chronically “leaky gut”, and, consequently, to a low-grade chronic systemic inflammation and dysregulated metabolism, and, as a result, a compromised blood-brain barrier and dysregulated immune responses. In such “disordered” conditions, toxins and pathogens, which are normally controlled by organismal defenses and inter-tissue barriers, may gain access to the brain, causing malfunction and degeneration of its susceptible regions and functions. Therefore, adequate diagnostic and treatment of multi-level malfunctioning networks, such as the human organism, require mapping out the structure of control relationships within and between different levels, followed by tracking down causal links from specific manifestations of a disease to the malfunctioning nodes and control relationships that are responsible for network failures.
The latest research by Dr. Kurakin revealed that chronic microdamage of brain tissue and ensuing microwounds that fail to heal may explain the progressive deterioration of neuronal connectivity and brain functions in AD. Tracking down primary culprits is underway.
Phase III Trial of an Investigational Drug
Photo: Edmond Teng, M.D., Ph.D.
The Katherine and Benjamin Kagan Alzheimer's Disease Treatment Development Program is continuing to participate in multi-center clinical trials that focus on developing new therapeutic interventions at earlier stages of Alzheimer’s disease. Among the exciting new trials that we are currently recruiting subjects for is the β-Amyloid Production and Effects on Cognition Study (APECS), which is examining the effects of the experimental drug MK-8931 (also known as verubecestat) in patients with mild cognitive impairment and prodromal Alzheimer’s disease. This study is sponsored by Merck and is being conducted at 187 research centers around the world.
MK-8931 is a drug that reduces the activity of a protein called β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which appears to play a key role in the production of β-amyloid (Aβ) peptide in the brain. Aβ is one of the primary features of Alzheimer’s disease and appears to damage to neurons and other brain cells.
MK-8931 is an oral medication. Prior studies in patients with Alzheimer’s disease suggest that this medication can dramatically reduce the production of brain Aβ production and is relatively well tolerated at the doses that are being used in this trial. It is currently being tested in a separate large Phase III trial of >2000 patients with mild-to-moderate Alzheimer’s dementia. However, other studies of interventions that target Aβ suggest that earlier intervention may produce more robust benefits. Therefore, one of the goals of APECS is to determine whether MK-8931 can delay or prevent dementia in patients with mild cognitive impairment, which represents one of the earlier stages of Alzheimer’s disease.
You may be eligible to join APECS if you:
Potential study participants will undergo brain imaging with both MRI scans (which provide information about the structure of the brain) and florbetapir PET scans (which provide information about how much amyloid protein is in the brain). Only individuals with elevated brain amyloid levels will be enrolled in the study, and those participants will receive daily doses of either MK-8931 or placebo for a 2-year period. They will also undergo periodic memory testing and MRI scans.
If you think you might be interested in volunteering for this study, please contact us at (310) 794-6191 or visit our website: www.eastonad.ucla.edu.
Clinical Research Opportunities
If you would like to advance Alzheimer's disease research, please consider participating at the Easton Center. Below are two current trials. For a complete list of enrolling studies, visit our website at www.eastonad.ucla.edu.