BrightFocus On Stage at Alzheimer’s Conference
Scientist Honored for Impact of His BrightFocus-Funded Work
BrightFocus grantee Tsuneya Ikezu, MD, PhD, of Boston University, is this year’s recipient of AAIC’s Inge Grundke-Iqbal Award for Alzheimer’s Research, an honor recognizing the senior author of the most impactful study published in Alzheimer's research over the preceding two years.
BrightFocus funded the work that led to Dr. Ikezu’s paper in Nature Neuroscience last October (Asai et al, 2015). A 20-year Alzheimer’s investigator, Ikezu was the mentor on a 2013-15 Alzheimer’s Disease Research grant to Hirohide Asai, MD, PhD, and then took over the project after Dr. Asai moved to a different institution.
In a personal statement, Dr. described how he got started in Alzheimer’s research.
“Alzheimer's disease (AD) is the most dominant senile brain disorder without cure, and captured my interest at the beginning of my research career,” he told BrightFocus. “I thought perhaps I can contribute a little to move the science forward.”
Their results provided new insights into how “bad tau” spreads and starts to take over the Alzheimer’s brain with “tau tangles,” or clusters of dead and dying nerve fibers. Ikezu and team showed that a damaged, toxic form of tau protein may spread from neurons in exosomes, or minute particles released from microglia, the brain’s innate immune cells. Exosomes are small, fluid-filled sacs that are released by microglia into the intracellular space, and from there they can be taken up by neurons.
While possibly not the only explanation of how tau tangles spread, the work by Ikezu and team covers new ground by demonstrating that tau can spread in a non-synaptic fashion. By offering this alternative explanation for tau’s early spread through exosomes, rather than adjacent neurons, they help to explain how AD may jump from one brain region to another as it progresses.
And they have also proposed closing this route, pharmacologically, suggesting that tau-carrying exosomes are a promising strategy to explore in drug development. Unlike amyloid plaques, which grow slowly over decades, tau tangles are associated with rapid progression and spread of AD.
Altogether, this BrightFocus-funded work has brought us most closer to understanding the mechanism by which Alzheimer’s takes over and destroys the brain, and how to stop it.
Dr. Ikezu has since received a 2016-18 ADR grant to further our understanding of another immune molecule, TREM2 [triggering receptor expressed on myeloid cells 2], which is found on the surface of immune cells and facilitates their uptake of protein fibrils and dead cells. It’s being explored as a possible target for drugs that might enhance the brain’s ability to protect itself by clearing away toxic debris.
Dr. Ikezu holds joint appointments in the Boston University Alzheimer’s Disease Center and its graduate program in neuroscience, where he leads the Laboratory of Molecular NeuroTherapeutics. His selection for the Inge Grundke-Iqbal Award was made by the AAIC Scientific Program Committee.
Tau Discoveries and Treatment Approaches
Alzheimer’s Disease Research (ADR) Scientific Review Committee (SRC) Chairman David Holtzman, MD, is featured as a top speaker at AAIC, with a talk entitled “Preclinical to Clinical Translation for Tau Therapeutics.” It focuses on the narrowing gap between what researchers have learned about the impact tau protein has on Alzheimer’s disease (AD), and being able to harness that knowledge for use in clinical interventions.
Discovery science funded by BrightFocus and others has shown that tau tangles may develop in the Alzheimer’s brain long after the development of amyloid beta plaques, but that this toxic, fibrous form of tau seems to greatly accelerate disease progression. Thus, it has become a target for new treatments that are under investigation.
Holtzman is professor and chair of neurology at Washington University in St. Louis; scientific director of its Hope Center for Neurological Disorders; and associate director of the Charles F. and Joanne Knight Alzheimer's Disease Research Center there. He assumed the chairmanship of the BrightFocus ADR committee in February, taking over from longtime chair Edward Koo, MD, who stepped down.
Stepping Inside the Alzheimer’s Home with Research Findings
More than two-thirds of all people with dementia (70 percent) live at home. For some, it’s their wish; for others, it’s the most cost-effective option; and for many, it’s the only option.
As Alzheimer’s numbers grow, the numbers of people aging in place will rise dramatically. And even more once drugs are available to delay AD progression, because then people will be living longer with relatively mild disease.
With home care rising beyond current projections, the question becomes, are we ready?
Aging in place with AD may, in fact, be the best option for many, and can be done successfully if the right support is there. New programs and research are being developed to address such things as needs assessment; medical care and specialists; innovative technology; access to community support; safety; and training for caregivers to help them deal with the stress and challenges that AD poses. However, research into the effectiveness of these various interventions and approaches is still young, scattered, and not easily accessible.
A BrightFocus-funded initiative is addressing that challenge. At AAIC, early results will be presented in a session entitled “Accelerating the Development, Testing and Dissemination of Home Based Dementia Care Interventions” led by BrightFocus Vice President for Scientific Affairs Diane Bovenkamp, PhD, and current grantee, Constantine Lyketsos, MD, director of psychiatry at Johns Hopkins Bayview Medical Center and director of its Memory and Alzheimer's Treatment Center. They will focus on the efforts of a consensus panel drawn from various disciplines whose members all have expertise in clinical trials and treatment for home-based dementia care. This BrightFocus-funded panel was first convened in December 2015 as a “pre-summit activity,” and a 2017 research summit is being planned. The resulting recommendations will be published and also taken before a national advisory committee for possible incorporation into the U.S. Alzheimer’s Plan.
Christopher Callahan, MD, Indiana University, is a general internist who’s studying ways to enable primary care physicians to deliver excellent care to older adults with dementia. His AAIC presentation focuses on dissemination challenges that stand in the way of widespread use of evidence-based, best practices in home dementia dementia care, and ways to overcome them.
Laura Gitlin, PhD, Johns Hopkins, is a nurse-researcher and founding director of the Johns Hopkins Center for Innovative Care in Aging. Her research focuses on non-pharmacological interventions and other methods of managing the symptoms of dementia. At AAIC she is presenting on “Accelerating the Development, Testing and Dissemination of Home-Based Dementia Care Interventions.”
Helen C Kales, MD, University of Michigan, is a geriatric psychiatrist who directs the Program for Positive Aging, Michigan Health System. She will be speaking about the “WeCare Advisor” an iPad administered algorithm, targeted to caregivers, to help them manage behavioral symptoms of dementia. The program is now being evaluated in a clinical trial.
Quincy Samus, PhD, Johns Hopkins, is a gerontologist specializing in epidemiology and health services research into the delivery of health services to older adults and families affected by dementia. She is a chief investigator with the Hopkins-based MIND clinical trial [Maximizing Independence at Home for People with Dementia], and her AAIC talk is focused that trial’s design, outcomes, and future directions.
MetLife Foundation Awards Have Many BrightFocus Connections
Thirty years ago, at a time when Alzheimer’s was just beginning to take root in the nation’s consciousness, the MetLife Foundation established an awards program recognizing outstanding researchers in the field.
Back then, in 1986, there were only 927 publications on Alzheimer’s disease (AD), according to George M. Martin, MD, scientific director emeritus of the American Federation for Aging Research (AFAR), which administers the awards. Since then the number has grown exponentially.
Also in the intervening years, 83 investigators have been honored from a diverse array of scientific disciplines. Among them are many current or past BrightFocus grantees.
This year, two of the four 2016 MetLife awardees are BrightFocus grantees.
Guojun Bu, PhD, of Mayo Clinic, Jacksonville, received a MetLife Major Award for Medical Research. The award carries a $100,000 institutional grant and a $25,000 personal prize. Bu is a member of the BrightFocus ADR Scientific Review Committee and editor of BrightFocus’ open-access journal, Molecular Neurodegeneration. He is a past BrightFocus grantee (2010-13 and 2006-08), and has mentored additional BrightFocus grantees.
MetLife cited Bu’s breakthrough studies focusing on a cell surface receptor known as low density lipoprotein receptor-related protein 1 (LRPI). He discovered that LRP1 plays a critical role in clearing toxic Aβ peptides that build up in AD brains. More recently, with his latest BrightFocus grant, Bu helping to connect the dots between diabetes and increased risk of AD through his work describing LRPI’s role in regulating insulin signaling.
“His team’s contributions to Alzheimer’s research rank among the most significant in the field,” MetLife announced. “Dr. Bu’s work exemplifies his ability to foster the collaborative, team-based science needed to facilitate … scientific discoveries from patients to the bench and back to patients in the form of effective treatments.”
John R. Cirrito, PhD, of Washington University School of Medicine in St. Louis, received one of two MetLife Promising Investigator Awards. He is a 2013-15 BrightFocus grantee.
“Dr. Cirrito’s work is relevant to any therapeutic strategies looking to enhance clearance of Aβ,” MetLife announced. They highlighted a technique he developed for measuring Aβ levels in the fluid surrounding brain cells, which allowed researchers to track those levels on an hourly basis in mice. This paved the way for additional research exploring cause and effect relationships between Aβ production/clearance and variables such as age, sleep patterns, levels of activity, and drug treatments. His protocol has since been adopted by eight other laboratories.
More recently, as part of his BrightFocus-funded project, Cirrito developed a new technology to measure Aβ clearance every 60 seconds. For the last 14 years we had a technique in which we would do something to the mouse – give it a drug, have it perform a certain behavior – and we’d find out what happened to its amyloid beta levels an hour later,” said Cirrito said in an interview. “Waiting that long just wasn’t good enough. Neural activity happens on a rapid time scale, and we needed to see a direct connection between the intervention and the amyloid beta levels.” This BrightFocus-funded discovery was published last May (Wang et al, J Experimental Med, 2016).
However, the primary focus of Cirrito’s BrightFocus grant was on the synapses, or junction between neurons, where communication takes place between cells. With his team, Cirrito showed that a process by which cells communicate can regulate Aβ levels in the brains of mice. Evidence suggests a similar process occurs in human brains as well. Last June, Cirrito et al published these results linking serotonin receptors and signaling to suppression of Aβ in brain interstitial fluid. The results open future avenues for therapy (Fisher et al, Mol Neurodegeneration, 2016).
His MetLife award comes with a $50,000 institutional grant.
Chairing the advisory committee for this year’s MetLife awards was David Holtzman, MD, chair of the BrightFocus Alzheimer’s Disease Research Scientific Review Committee (ADR SRC), and professor and chair of neurology at the Washington University School of Medicine in St. Louis Also serving on the committee was outgoing BrightFocus ADR SRC Chair Edward H. Koo, MD, professor of neuroscience at the University of California, San Diego.
“When scientists receive a MetLife Foundation award, it tells the world they have made contributions have fundamentally changed our understanding of Alzheimer’s disease,” commented Dr. Holtzman in the awards brochure.
Results from BrightFocus Grant Projects Shared at AAIC
Many thanks to the following grantees who wrote to say they are presenting results at AAIC related to their BrightFocus-funded projects. Congratulations on sharing your work at this important venue!
David Brody, MD, PhD, 2014-17 grantee at Washington University School of Medicine in St. Louis (MO) who’s studying toxic forms of amyloid beta (Aβ ), perhaps more closely than anyone has before, in order to identify and purify those Aβ strains associated with Alzheimer’s disease (AD) in humans. So far he’s found more than 12 s, whereas most drug development efforts are focused on only two toxic Aβ species, Aβ40 and Aβ42. (AAIC Abstract P1-099)
Carlos Cruchaga, PhD, 2014-16 grantee at Washington University in St. Louis (MO), whose genetic research employs a novel statistical analysis method (Mendelian Randomization) to analyze genes and proteins in cerebrospinal fluid that are involved in AD , with the goal of contributing to biomarkers for for diagnosis and new drug targets for treatment. As part of the project, he’s using big-data techniques to analyze more than 7 million genetic variants and 16,000 genes.
M. Paul Murphy, PhD, 2014-17 grantee at University of Kentucky (Lexington), who is studying the comorbidities between AD and cardiovascular disease in a unique mouse model. (AAIC Abstract P413)
Rik Ossenkoppele, PhD, 2014-17 grantee at VU University Medical Center, Amsterdam, who is using positron emission tomography (PET) scanning to study relationships between tau pathology and other AD pathologies, including Aβ, brain shrinkage, and impaired communication among brain cells. His AAIC oral presentation was entitled "Tau Covariance Patterns in Alzheimer's Disease Patients Resemble Intrinsic Connectivity Networks in Young Adults.”
Mitsuru Shinohara, PhD, 2014-16 grantee at Mayo Clinic Jacksonville (FL), whose research focuses on the role that synapses (neuronal connections in brain) have on Aβ production and accumulation. The goal is to identify appropriate biomarkers that indicate disturbances in synaptic Aβ metabolism before the onset of AD. (AAIC Poster #10546)
Eugenia Trushina, PhD, 2011-14 grantee at Mayo Clinic in Rochester, MN, whose research focuses on the relationship between mitochondrial trafficking, function and memory. Her project clarified the role of histone deacetylase 1 (HDAC1), a protein regulating gene activity, in promoting neural cell death by disrupting movement of the mitochondria, the cell's “energy powerhouses,” thus providing a mechanistic rationale for the development of HDAC inhibitors as a potential AD therapy. (AAIC Abstracts #6823, #635335)
Hongmin Wang, PhD, 2014-17 grantee at the University of South Dakota in Vermillion, SD, who’s using a genetically modified mouse model to study the role of ubiquilin-1, a protein long associated with AD. Its role is to assist cells in removing unwanted proteins, such as toxic Aβ Dr. Wang and team are investigating how both an increase and decrease of ubiquilin-1 protein levels alters AD symptoms and progression, brain tissue structures, and the breakdown of AD-related proteins. (AAIC Poster #P4-267)