DSRTF proudly announces the award of new 2012-2013 Research Grants to fund leading researchers from major research centers around the country to help accelerate the delivery of treatments to improve cognition, including learning, memory and speech for individuals with Down syndrome. Recipients of these awards include researchers at Johns Hopkins University School of Medicine for their work with a network of institutions participating in the Down Syndrome Cognition Project, the University of California, San Diego School of Medicine, the University of Arizona, Stanford University, the VA Palo Alto Health Care System, and the University of Texas, Austin.
With the funding of its 2012-2013 DSRTF Research Grants, DSRTF has now provided over $9 million to advance Down syndrome cognition research.
JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
DSRTF Research Center Grant: “A Down Syndrome Virtual Center for Basic and Translational Studies-Cognition and Therapy in Down Syndrome”; Principal Investigators Roger Reeves, Ph.D., Professor, Department of Physiology and McKusick Nathans Institute for Genetic Medicine, and Stephanie Sherman, Ph.D., Professor, Department of Human Genetics Emory University School of Medicine.
Co-Principal Investigators include Lynn Nadel, Ph.D. and Jamie Edgin, Ph.D. (University of Arizona); Paul Worley, M.D., David Foster, Ph.D. and Valerie DeLeon, Ph.D. (Johns Hopkins University School of Medicine); George Capone, M.D. and Iser DeLeon, Ph.D. (Kennedy Krieger Institute, Baltimore); Eleanor Feingold, Ph.D. (University of Pittsburgh); Cheryl Maslen, Ph.D. (Oregon Health and Science University); Len Abbeduto, Ph.D. (MIND Institute, University of California, Davis); Marsha Seltzer, Ph.D. (Waisman Center, Madison, WI); and, Emily Kuschner, Ph.D./Anne Inge, Ph.D. (Children’s National Medical Center, Washington DC)
A key feature of Down syndrome (DS) is the high degree of variability in presentation of the various common phenotypes, especially including cognition, learning, memory and speech that characterize the syndrome. The studies will extend and expand the multi-year Down Syndrome Cognition Project (DSCP) which is employing the Arizona Cognitive Test Battery (ACTB) with a sizeable cohort of individuals with Down syndrome to accurately assess and define variability in cognitive ability and genetic differences, identify targets for therapeutic interventions, develop related registry and biobank components, and further establish a network of collaborating clinical sites as an important scaffold for a clinical trials network. Development, validation and incorporation of a language acquisition testing component will also enhance the assessments. As a major goal is to develop effective new therapies to improve cognition in individuals with DS it is important to understand how divergence from typical structure and function occur in DS mouse models, and to provide model systems for testing pharmacological interventions. To further address this, additional laboratory-based projects will further investigate: 1) The mechanistic basis by which a single-dose treatment with a specific SHH growth factor-like drug, SAG, early in life of a mouse model of DS restores cerebellar and hippocampal function involving learning and memory in adults; 2) The mechanisms involved in hippocampal neural circuit/network dysfunction, particularly in inhibitory-excitatory imbalance and effects of GABA-A receptor blocking drugs and characterization of potential biomarkers related to cognition; and, 3) The role of reduced Narp (neuronal activity-regulated pentraxin) expression in abnormal synaptic transmission and whether this may play a role in sustaining GABA-A receptor-mediated improvement in cognition in DS.
UNIVERSITY OF CALIFORNIA, SAN DIEGO SCHOOL OF MEDICINE
DSRTF Research Center Grant: “Defining the Genes and Mechanisms Causing Neurodegeneration in Down Syndrome (DS) and Discovering Effective Treatments”; Principal Investigator William Mobley, M.D., Ph.D. Professor and Chair, Department of Neurosciences and Director, UCSD Down Syndrome Center for Research and Treatment.
Co-Principal Investigators include Pavel Belichenko, M.D., Ph.D., Alexander Kleschevnikov, Ph.D., Steve Wagner, Ph.D. and Chengbiao Wu, Ph.D.
An ultimate goal is to determine the pathogenesis of cognitive deficits in the developing and aging brain of people with Down syndrome (DS) and to define treatments to enhance cognition in people with this disorder and to prevent the onset in later life of Alzheimer disease (AD). The underlying rationale is the ‘gene-dosage hypothesis’: all the changes in people with DS are caused by the presence in excess of one or more genes or regulatory sequences on chromosome 21. As Alzheimer’s disease is essentially inevitable in people with DS, these studies will further focus on the genes and mechanisms responsible for age-related neurodegeneration that link defects in endosomal trafficking to the loss of neuronal populations important for cognitive function. The hypothesis that guides this research is that: increased dosage of APP and an as yet undefined additional gene(s) results in endosomal pathway and neurotrophic signaling dysfunction with resulting synaptic and cellular dysfunction and dementia. Using mouse models of DS and human DS-specific iPSCs (induced pluripotent stem cells derived from patients’ skin cells) the proposed research will: 1) Define additional chromosome 21 gene(s), e.g. Girk2, Dryk1A, Tiam1, RCAN1, and/or Synj1, potentially responsible for disrupting endosomal traffic through an increase in Rab5 and altered neurotrophic (BDNF/TrkB) signaling; 2) Discern the mechanisms by which APP and other genes act to disrupt endosomal trafficking; 3) Define the behavioral and physiological significance of endosomal traffic disruption; and 4) Investigate treatments to prevent or reverse disruption, including the use of soluble gamma-secretase modulators (sGSM) to modify processing of APP, and to show that such treatments prevent or reverse changes in endosomal trafficking and neuronal dysfunction and degeneration. An additional project will contribute to development of “21Lab”, as a comprehensive, researcher-driven and universally available web-based DS research platform, for sharing and exchange of DS research data, information, reagents, critical analysis and collaborations by the DS research community to enhance and accelerate research progress.
UNIVERSITY OF ARIZONA
DSRTF Innovation Research Grant: “The Neuropsychology of Down Syndrome”; Principal Investigators Lynn Nadel, Ph.D., Regent’s Professor and Jamie Edgin, Ph.D., Assistant Professor, Department of Psychology and Co-Directors, University of Arizona Down Syndrome Research Group.
An overarching goal is to uncover the etiological factors, i.e., genetic, neurological, medical, environmental, that lead to variation in the cognitive phenotype of Down syndrome (DS). Identifying the factors influencing this variability may be central to the formulation of successful treatments for cognitive difficulties in DS. In collaboration with the DS research community at large and more recently pharmaceutical companies, this research laboratory has been involved in the development of reliable and valid assessments of key components of the cognitive and behavioral phenotype associated with Down syndrome. The first DS-specific assessment instrument, the Arizona Cognitive Test Battery (ACTB), is appropriate for individuals older than 10 years of age and has now been validated and published. The current and proposed goals are to apply and expand this instrument in three directions: 1) Further the development of state-of-the art cognitive assessment batteries for use with toddlers and young children with DS; 2) Further defining the profile of cognitive function in DS, including the integrity of parahippocampal cortex; 3) Evaluate contextual object memory involving medial temporal lobe function and investigate establishment of biomarkers for cognitive function in DS that build on and correlate with the cognitive assessment instrument, using EEG and evoked potential methodologies; and, 4) Develop a companion instrument that will assess language and general communicative functions . In addition to these specific goals, the ACTB will continue to be used in ongoing studies of sleep disturbance in DS. Taken together, the proposed projects will expand the ACTB and its applications, allowing researchers to be better positioned to conduct more effective clinical trials in this population.
STANFORD UNIVERSITY SCHOOL OF MEDICINE
DSRTF Innovation Research Grant: “Mechanisms Underlying the Roles of Sleep and Circadian Rhythms in the Learning Disability of Down Syndrome”; Principal Investigator Dr. H. Craig Heller, Ph.D., Lokey/Business Professor Department of Biology, and co-Principal Investigator Dr. Craig Garner, Ph.D., Professor Department of Psychiatry and Behavioral Sciences, and Co-Directors Stanford Down Syndrome Research Center.
Prior research has demonstrated that the learning disability of Ts65Dn mice, a mouse model for Down syndrome, can be dramatically reduced, long-term, following a short-term regimen of chronic dosing with GABA-A antagonists such as pentylenetetrazole (PTZ). However, the mechanism whereby the GABA-A antagonism is creating this long-term alteration of neuroplasticity remains incompletely defined. Previous research also established that alterations in sleep and circadian rhythms are involved in both the disability and the drug effects. The proposed studies will investigate how the DS related features of circadian rhythms and sleep are influencing learning and memory in Ts65Dn mice and how pharmacotherapy is altering those relationships. It has been established that when mice are trained in the light phase, sleep during the subsequent 4 hrs is critical for memory formation. To further investigate this, a detailed quantitative study of the EEG will be performed during that 4 hrs in Ts65Dn and control mice before and after chronic PTZ treatment. It will also be determined whether the Ts65Dn mice have sleep apnea that could compromise their quality of sleep. To investigate the role of the circadian system, lesioning and pharmacogenetic methods will be used to evaluate the effects of increasing or decreasing brain SCN (suprachiasmatic nucleus) activity at different circadian phases on memory formation. Two practical outcomes from this research could be expected: 1) understanding mechanisms may lead to alternative treatment strategies, and 2) the results could provide insights into potential new biomarkers that can be used to assess treatment efficacy in humans.
VA PALO ALTO HEALTH CARE SYSTEM
DSRTF Innovation Research Pilot Grant: “Improving Adrenergic Signaling for the Treatment of Cognitive Dysfunction in Down Syndrome”; Principal Investigator Ahmad Salehi, M.D., Ph.D., Research Health Science Specialist and Clinical Associate Professor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine.
Down syndrome (DS) is associated with significant learning disabilities. The proposed research aims to continue to develop new therapeutic strategies, focused on increasing norepinephrine (NE) levels to improve cognition, using mouse models of DS. In recent studies it was found that the degeneration of the norepinephrine (NE) system, particularly in the locus coeruleus (LC), in the brain of DS model Ts65Dn mice can be linked to contextual learning failure in these mice. Analogous degeneration of the NE system has also been observed in Alzheimer’s disease. The research in the DS mouse model also indicated that increasing brain NE levels, using an NE precursor, L-DOPS, or NE agonists, could significantly improve cognitive function. In the ongoing project, the effects of increasing brain NE levels and/or improving β-adrenergic receptor signaling to restore cognition in Ts65Dn mice is being tested. The research has shown that atomoxetine (ATMX; an approved NE-reuptake inhibitor) alone does not improve cognition in these mice; however, administration of ATMX together with significantly lower doses of L-DOPS does improve learning and memory. Improvement in learning and memory has also been demonstrated with administration of only formoterol, an adrenergic b2 NE agonist approved for use in respiratory disorders. Preliminary results also indicate formoterol may increase neurogenesis in the hippocampus. The proposed research will: 1) Determine the minimum effective dose of L-DOPS and ATMX needed to restore cognitive function in Ts65Dn mice; 2) Define the effects of the b2 NE agonist formoterol on acquisition versus retrieval of memory in young adult Ts65Dn mice; and, 3) Further investigate mechanisms by which formoterol through b2 signaling may positively impact hippocampal neurogenesis and/or alters neurodegeneration and improves cognition in mouse models of DS. These studies will significantly contribute to advancing research and development of potential NE- based therapies for cognitive disabilities in DS, including aspects related to Alzheimer’s disease.
UNIVERSITY OF TEXAS, AUSTIN
DSRTF Innovation Research Pilot Grant: “Molecular Analysis of Proneurogenic, Neuroprotective Drugs on Prevention of APP-induced Neurodegeneration in a Model of Down Syndrome”; Principal Investigator Jon Pierce-Shimomura, Ph.D., Assistant Professor, Section of Neurobiology.
In DS, an extra copy of the APP gene on human chromosome 21 contributes to the pathology associated with Alzheimer’s disease (AD) and the degeneration of a specific subset of cholinergic neurons important for memory. Study of age-related neurodegeneration caused by APP in mouse models can be complicated, so a model using C. elegans, a simpler experimental organism, has been developed. It has been shown that adding an extra copy of the APP gene causes degeneration of a subset of cholinergic neurons in middle age in C. elegans just as in human DS and AD. Through genetic and pharmacological analyses, it has been discovered that serotonin is both necessary and sufficient for APP- induced neurodegeneration in C. elegans. Two serotonergic drugs have been shown to prevent the degeneration in C. elegans and resemble a drug candidate investigated in human AD called Dimebon. It has recently found that neurodegeneration in C. elegans is also prevented by Dimebon. Intriguingly, Dimebon has also been shown to promote the survival (prevent the death) of neurons that are naturally born in adult brain and involved in memory in mice and humans. However, the molecular mechanism by which Dimebon and related drugs prevent the death of neurons is unknown. Genetic and pharmacological approaches are being used to test this hypothesis by investigating whether other drugs known to promote survival of adult-born neurons in mouse may also prevent APP-induced neurodegeneration in C. elegans, how Dimebon and these related drugs work at the molecular level, and whether the neuroprotective effects of Dimebon are negated by other serotonergic drugs – possibly explaining mixed results for Dimebon in clinical trials. Answers to these questions have the potential to impact the treatment of adults with DS.