Neuroplasticity, Neuroregeneration, and Brain Repair

Available via

WEBINAR

Neuroplasticity, Neuroregeneration, and Brain Repair

Tuesday, June 13, 2017 - Wednesday, June 14, 2017

The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York, USA

Presented By

Eli Lilly and Company

The New York Academy of Sciences

 

Strategies to stimulate neuroregeneration and neurorestoration hold promise to vastly improve the treatment of a range of neurological diseases and injuries, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal cord injury, and multiple sclerosis (MS). While progress has been made in understanding the cellular mechanisms of these processes, more research is needed in order to translate this knowledge into more effective treatments that restore function to the central nervous system.

This 2-day convening will bring together leading researchers, clinicians, industry, and governmental stakeholders from around the world to explore neuroregenerative processes and identify strategies for translating knowledge into treatments for neurodegenerative diseases and nervous system injuries. Plenary sessions will be designed to present emerging basic and clinical research in the following areas: neurodegenerative disease-modifying therapies that slow progression; mechanisms of neuroplasticity, including the role of dendritic spines, axonal growth, synaptic plasticity, inflammation, oxidative stress, mitochondrial function, and autophagy; glial function in the central nervous system; cutting-edge strategies to promote and modify neurogenesis; and biomarker and imaging modalities for neuroregeneration. The conference will conclude with an interactive panel discussion exploring future directions, critical open questions, and promising therapies in the field of neuroregeneration and neurorestoration.

Registration includes a complimentary, one-year membership to the New York Academy of Sciences. Complimentary memberships are provided to non-members only and cannot be used to renew or extend existing or expiring memberships. A welcome email will be sent upon registration which will include your membership credentials.

Registration

Member
By 05/01/2017
$220
After 05/01/2017
$265
Onsite
$300
Nonmember Academia, Faculty, etc.
By 05/01/2017
$355
After 05/01/2017
$395
Onsite
$435
Nonmember Corporate, Other
By 05/01/2017
$435
After 05/01/2017
$500
Onsite
$565
Nonmember Not for Profit
By 05/01/2017
$355
After 05/01/2017
$395
Onsite
$435
Nonmember Student, Undergrad, Grad, Fellow
By 05/01/2017
$170
After 05/01/2017
$200
Onsite
$245
Member Student, Post-Doc, Fellow
By 05/01/2017
$115
After 05/01/2017
$145
Onsite
$190
Member
$55
Nonmember Academia, Faculty, etc.
$90
Nonmember Corporate, Other
$110
Nonmember Not for Profit
$90
Nonmember Student, Undergrad, Grad, Fellow
$40
Member Student, Post-Doc, Fellow
$30

Day 1: Tuesday, June 13, 2017

8:00 AM

Registration, Continental Breakfast, and Poster Session Setup

8:45 AM

Opening Remarks
Alison Carley, PhD, The New York Academy of Sciences
David Bleakman, PhD, Eli Lilly and Company

 

9:00 AM

Keynote Address
Astrocytes in Central Nervous System Repair and Regeneration
Michael V. Sofroniew, MD, PhD, David Geffen School of Medicine at the University of California, Los Angeles

Session I: Mechanisms of Neuroplasticity and the Role of Dendritic Spines, Axonal Growth, and Synaptic Plasticity

Session Chair: Mark P. Mattson, PhD, National Institute of Aging, National Institute of Health

9:45 AM

Regulation of Synapses and Synaptic Strength
Richard Tsien, DPhil, New York University Langone Medical Center

10:15 AM

Striatal Plasticity in Parkinson's Disease
James Surmeier, PhD, Feinberg School of Medicine, Northwestern University

10:45 AM

Networking Coffee Break

11:15 AM

Novel Mechanisms of Immune-mediated Nervous System Regeneration
Roman J. Giger, PhD, University of Michigan School of Medicine

11:45 AM

Subtype-specific Local Growth Cone Control over Circuit Development, Regeneration, and Degeneration
Jeffrey Macklis, MD, DHST, Harvard University

*This talk will not be available on Webinar

12:15 PM

Networking Lunch

Session II: Mechanisms of Neuroplasticity and the Role of Inflammation, Oxidative Stress, Mitochondrial Function, and Autophagy

Session Chair: Clive Svendsen, PhD, Cedars-Sinai Medical Center

2:00 PM

Intermittent Bioenergetic Challenges Bolster Brain Resilience
Mark P. Mattson, PhD, National Institute of Aging, National Institute of Health

2:30 PM

Malfunctioning Autophagy and its Pathway to Neurodegeneration
Ana Maria Cuervo, MD, PhD, Albert Einstein College of Medicine

3:00 PM

Mitochondrial-linked Mechanisms and Therapeutic Opportunities
Valina L. Dawson, PhD, Johns Hopkins University

3:30 PM

Networking Coffee Break

Session III: Glial Function in the Central Nervous System

Session Chair: Jeffrey Macklis, MD, DHST, Harvard University

4:00 PM

Human Glial Progenitor Cell-based Treatment and Modeling of Neurological Disease
Steven A. Goldman, MD, PhD, University of Rochester Medical Center

4:30 PM

Stem Cell-derived Astrocytes for the Treatment Neurodegenerative Diseases
Clive Svendsen, PhD, Cedars-Sinai Medical Center

5:00 PM

Development of Functionally Heterogeneous Astrocytes in Mammalian Central Nervous System
David H. Rowitch, MD, PhD, ScD, University of Cambridge, United Kingdom

5:30 PM

Networking Reception and Poster Session

6:30 PM

Day 1 Adjourns

Day 2: Wednesday, June 14, 2017

8:00 AM

Continental Breakfast

Session IV: Disease-modifying Therapies that Slow Disease Progression

Session Chair: Michael J. O'Neill, PhD, Eli Lilly and Company

8:50 AM

Industry Perspective Lecture
Disease-modifying Drugs for Alzheimer's Disease — The Past and The Future
Eric Karran, BSc, PhD, AbbVie

Session V: Innovative Approaches to Modify Neurogenesis and to Promote Neuroregeneration

Session Chair: David Bleakman, PhD, Eli Lilly and Company

9:30 AM

Is Alzheimer's Disease Caused by Long-term Depression Gone Awry?
 Graham Collingridge, FRS, FMedSci, FSB, FBPhS, University of Toronto, Canada

10:00 AM

Modeling Human Brain Development and Disorders using Human Induced Pluripotent Stem Cells (hiPSCs)
Guo-li Ming, MD, PhD, University of Pennsylvania

10:30 AM

Networking Coffee Break

11:00 AM

Engineering of Neurogenesis via Lineage Reprogramming
Benedikt Berninger, PhD, University Medical Center Johannes Gutenberg University Mainz, Germany

11:30 AM

Rejuvenating and Re-engineering Aging Memory Circuits
Amar Sahay, PhD, Massachusetts General Hospital

12:00 PM

Networking Lunch

Session VI: Hot Topic Talks from Submitted Abstracts

Session Chair: Alison Carley, PhD, The New York Academy of Sciences

1:30 PM

In Vivo Two-photon Imaging of the Effects of Tauopathy and Amyloidopathy on Synapse Dynamics
Johanna Jackson, PhD, Eli Lilly and Company

1:50 PM

Integrative Bioinformatics Approach to Understand the Role of Plasticity in Neurodegenerative Disease
Milo Robert Smith, Icahn School of Medicine at Mount Sinai

2:10 PM

Testing Hereditary Spastic Paraplegia Genes for Roles in Modeling Axonal Endoplasmic Reticulum in Drosophila
Eliška Zlámalová, University of Cambridge, United Kingdom

Session VII: Biomarkers and Imaging Modalities for Neuroregeneration

Session Chair: David Bleakman, PhD, Eli Lilly and Company

2:30 PM

Neuroimaging Studies for the Early Detection of Alzheimer's Disease
Reisa A. Sperling, MD, MMSc, Brigham and Women's Hospital

3:00 PM

Neuronal Dysfunction in Mouse Models of Alzheimer's Disease In Vivo
Arthur Konnerth, PhD, Technical University of Munich, Germany

3:30 PM

Networking Coffee Break

Session VIII: The Future of Research and Therapies in Neuroregeneration and Neurorestoration

Session Chair: Michael J. O'Neill, PhD, Eli Lilly and Company

4:00 PM

Interactive Panel Discussion with Audience Q&A
 
Moderator:Michael J. O'Neill, PhD, Eli Lilly and Company 

Panelists:
Ana Maria Cuervo, MD, PhD, Albert Einstein College of Medicine
Mark P. Mattson, PhD, National Institute of Aging, National Institute of Health
Clive Svendsen, PhD, Cedars-Sinai Medical Center
Jeffrey Macklis, MD, DHST, Harvard University

4:50 PM

Closing Remarks
Daniel Skovronsky, MD, PhD, Eli Lilly and Company
Alison Carley, PhD, The New York Academy of Sciences

 

5:00 PM

Conference Adjourns

 

Speakers

Keynote Address

Michael V. Sofroniew, MD, PhD

David Geffen School of Medicine at the University of California, Los Angeles

Dr. Michael Sofroniew's professional career has been devoted to understanding the cell biology of injury and repair in the adult central nervous system (CNS). He is currently a Distinguished Professor of Neurobiology at the University of California Los Angeles (UCLA). A main focus of work in his laboratory is dissecting astrocyte roles and mechanisms in CNS injury and disease, and how these impact on regulation of CNS inflammation, tissue protection, tissue repair and maintenance or recovery of function after diverse CNS insults. Studies combine transgenic mouse models with experimental models of CNS trauma, degenerative disease and autoimmune inflammation. He was raised in Los Angeles, Tokyo and Munich. He received an MD degree from Ludwigs-Maximillians University in Munich, Germany and a PhD (DPhil) from Oxford University, England and was surgical intern at Johns Hopkins University Hospital, Baltimore. He then became a faculty member at Cambridge University, England from 1986-2000 before moving to UCLA in 2000. He received the Demuth Young Scientist Award from the International Brain Research Organization and is in the Thomson-Reuters Web of Science top 1% of cited researchers in neuroscience.

Session I: Mechanisms of Neuroplasticity and the Role of Dendritic Spines, Axonal Growth, and Synaptic Plasticity

Session Chair: Mark P. Mattson, PhD, National Institute of Aging, National Institute of Health

Richard Tsien, DPhil

New York University Langone Medical Center

Richard W. Tsien, DPHIL, is Druckenmiller Professor of Neuroscience and Neural Science, Director of the New York University Neuroscience Institute, and Chair of the Department of Physiology and Neuroscience at the New York Univeristy Langone Medical Center (NYULMC). Prior to joining NYULMC, Dr. Tsien served as the George D. Smith Professor of Molecular Genetic Medicine at Stanford University. While there, Dr. Tsien founded and served as the inaugural chair of the Department of Molecular and Cellular Physiology. After a six-year term as chair, in 1994 he led a successful Stanford-wide movement to establish an institute for neuroscience, the Stanford Brain Research Center, which he co-directed from 2000 through 2005. He served a 10-year term as the director and principal investigator at Stanford's Silvio Conte Center for Neuroscience Research.

As a scientist, Dr. Tsien is a world leader in the study of calcium channels and their signaling targets, particularly at pre- and postsynaptic sites. He studies how synapses contribute to neuronal computation and network function in both healthy and diseased brains. His research, generously supported by the NIH and private foundations, has contributed substantially to understanding how neurotransmitters, drugs and molecular alterations regulate calcium channels and has implications for diverse clinical areas (such as pain and autism). His research has been published in over 200 peer-reviewed journals, and he has served on editorial boards for numerous journals.

He has also served as section chair for the American Association for the Advancement of Science (Neuroscience Section) and the National Academy of Sciences (Neurobiology Section). He has also been a member of scientific advisory boards for several institutes, including the Howard Hughes Medical Institute.

Dr. Tsien received both an undergraduate and graduate degree in electrical engineering from the Massachusetts Institute of Technology. He was a Rhodes Scholar, graduating with his doctorate in biophysics from Oxford University, England, after which he joined the faculty at Yale University School of Medicine, serving for nearly two decades. He is a member of both the Institute of Medicine and National Academy of Sciences.

James Surmeier, PhD

Feinberg School of Medicine, Northwestern University

Dr. D. James Surmeier is the Nathan Smith Davis Professor and Chair of the Department of Physiology at the Feinberg School of Medicine at Northwestern University and Director of the Morris K. Udall Research Center of Research Excellence for Parkinson's disease at Northwestern University. Dr. Surmeier received his Ph.D., in Physiology and Biophysics from the University of Washington in 1983. In 1998, he moved to the Department of Physiology at Northwestern University and assumed his current position in 2001. Dr. Surmeier's research program focuses on the basal ganglia — neural structures controlling movement and intimately involved in the pathophysiology of Parkinson's and Huntington's diseases. He was elected as a Fellow of the American Association for the Advancement of Science and has received many other scientific awards including the NARSAD Established Investigator award, the Riker Award, the Picower Foundation Award, Jacob Javits Neuroscience Investigator Award and BAM Patient Impact Research Award, Keynote Lecture Gordon Conference on Parkinson's Disease, Keynote Lecture Gordon Conference on Basal Ganglia, C. David Marsden Lecture, F.E. Bennett Memorial Lectureship Award, and Keynote Parkinson's UK Research Conference.

Roman J. Giger, PhD

University of Michigan School of Medicine

Roman Giger is a Professor in Cell and Developmental Biology at the University of Michigan School of Medicine. His research is focused on molecular and cellular mechanisms that regulate nervous system regeneration following injury or disease. To study gene function in the mammalian nervous system, the Giger laboratory pursues a variety of mouse genetic approaches combined with surgical, histological, biochemistry-based, electrophysiological, and behavioral studies. These investigations have led to the identification of novel ligands and receptors that orchestrate neural network assembly, axonal regeneration, myelin development, and synaptic plasticity in the mammalian central nervous system.

Jeffrey Macklis, MD, DHST

Harvard University

Macklis is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University, and Professor of Neurology [Neuroscience] at Harvard Medical School, and was founding Program Head, Neuroscience, Harvard Stem Cell Institute. He is an M.I.T. faculty member in the Harvard-Massachusetts Institute of Technology (M.I.T.) Division of Health Sciences and Technology. His lab is directed toward both: 1) understanding molecular controls and mechanisms over neuron sub-type specification, development, diversity, axon guidance-circuit formation, and degeneration in the cerebral cortex; and 2) applying developmental controls toward both brain and spinal cord regeneration and directed differentiation for in vitro therapeutic and mechanistic screening. The lab focuses on neocortical projection neuron development and sub-type specification; neural progenitor / “stem cell” biology; induction of adult cortical neurogenesis; subtype-specific axonal growth cone biology; and directed neuronal subtype differentiation via molecular manipulation of neural progenitors and pluripotent cells (ES/iPS). He is the recipient of a number of awards, including a Rita Allen Foundation Scholar Award, a Director's Innovation Award from the NIH Director's Office, The CNS Foundation Award, a Senator Jacob Javits (MERIT) Award in the Neurosciences from NINDS/NIH, The Cajal-Krieg Cortical Discoverer Prize, and he is an Allen Distinguished Investigator of the Paul G. Allen Family Foundation, and a Brain Research Foundation Fellow.

Session II: Mechanisms of Neuroplasticity and the Role of Inflammation, Oxidative Stress, Mitochondrial Function, and Autophagy

Session Chair: Clive Svendsen, PhD, Cedars-Sinai Medical Center

Mark P. Mattson, PhD

National Institute of Aging, National Institute of Health

After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders-Brown Center on Aging at the University of Kentucky College of Medicine where he advanced to Full Professor. In 2000, Dr. Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine. Dr. Mattson's research is aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. His work has elucidated how the brain responds adaptively to challenges such as fasting and exercise, and he has used that information to develop novel interventions to promote optimal brain function throughout life. Dr. Mattson is among the most highly cited neuroscientists in the world with an ‘h' index of over 190. He has received many awards including the Metropolitan Life Foundation Medical Research Award and the Alzheimer's Association Zenith Award. He was elected an AAAS Fellow in 2011. He is Editor-in-Chief of Ageing Research Reviews and is a Reviewing or Associate Editor for the Journal of Neuroscience, Trends in Neurosciences, the Neurobiology of Aging, and Aging and Mechanisms of Disease.

Ana Maria Cuervo, MD, PhD

Albert Einstein College of Medicine

Ana Maria Cuervo is the R.R. Belfer Chair for Neurodegenerative Diseases, Professor in the Departments of Developmental and Molecular Biology and of Medicine of the Albert Einstein College of Medicine and co-director of the Einstein Institute for Aging Studies. She obtained her MD and a PhD in Biochemistry and Molecular biology from the University of Valencia (Spain) and received postdoctoral training at Tufts University, Boston. In 2002, she started her laboratory at the Albert Einstein College of Medicine, where she continues her studies in the role of protein-degradation in neurodegenerative diseases and aging.

Dr. Cuervo has received prestigious awards such as the P. Benson and the Keith Porter in Cell Biology, the Nathan Shock Memorial Lecture, the Vincent Cristofalo and the Bennett J. Cohen in basic aging biology and the Marshall Horwitz and the Saul Korey Prize for excellence in research and in Translational Medicine. She delivered prominent lectures such as the Robert R. Konh, the NIH Director's, the Roy Walford, the Feodor Lynen, the Margaret Pittman, the IUBMB Award, the David H. Murdoxk, the Gerry Aurbach and the Harvey Society Lecture. She is currently co-Editor-in-Chief of Aging Cell and has been member of the NIA Scientific Council and of the NIH Council of Councils.

Valina L. Dawson, PhD

Johns Hopkins University

Valina L. Dawson, PhD, is a Professor of Neurology, Neuroscience, Physiology and the Graduate Program in Cellular & Molecular Medicine. She is co-director of the Neuroregeneration and Stem Cell Programs in the Institute for Cell Engineering. She has had a long-standing interest in mechanisms of neuronal cell death. She described for the first time that NO mediated glutamate neurotoxicity. In a series of studies she described the activation and regulation of nNOS in terms of neurotoxicity, and identified poly(ADP-ribose) polymerase (PARP-1) as a potential downstream target mediating neurotoxicity. Additionally, this team conducted experiments that showed that endogenously produced peroxynitrite is likely the nitrogen oxide moiety that mediates, in large part, NO neurotoxicity.

In 1994, Dr. Valina L. Dawson joined the Department of Neurology at the Johns Hopkins University School of Medicine where she has continued to define the conditions under which NO is neurotoxic as well as define conditions in which NO is not neurotoxic and likely plays a role as a neuromodulator.

She has performed experiments describing the neurotoxic actions of iNOS and correlated this with the progression and severity of AIDS dementia. nNOS neurons, which produce neurotoxic quantities of NO, are themselves resistant to toxicity. She described increased expression of MnSOD as one factor contributing to nNOS neuronal resistance to NO neurotoxicity and excitotoxic mechanisms.

Recently her group has been instrumental in uncovering the role of AIF in mediating PARP-1 dependent neurotoxicity. Dr. Dawson has contributed significantly to the field of neurotoxicity and has published over 260 full-length manuscripts and review articles, many with high citation impact. She showed that DJ-1 is an atypical peroxidoxine like peroxidase and showed that LRRK2 possesses kinase activity and disease causing mutations in LRRK2 lead to cell death that is kinase-dependent. Recently she identified drugs that block the neurotoxicity caused by LRRK2. These studies are providing major insights into understanding the pathogenesis of Parkinson's disease and are providing novel opportunities for therapies aimed at preventing the degenerative process of Parkinson's disease.

Session III: Glial Function in the Central Nervous System

Session Chair: Jeffrey Macklis, MD, DHST, Harvard University

Steven A. Goldman, MD, PhD

University of Rochester Medical Center

Dr. Steven A. Goldman is Professor of Neuroscience and Neurology at the University of Copenhagen and Executive Director of its Center for Neuroscience, as well as a Consultant at the Copenhagen University Hospital. He is also the URMC Distinguished Professor of Neuroscience and Neurology at the University of Rochester Medical Center in the US, co-director of its Center for Translational Neuromedicine, and an attending neurologist at URMC-Strong Memorial Hospital. Goldman moved to Rochester in 2003 from the Weill Medical College of Cornell University. A summa cum laude graduate of the University of Pennsylvania, he obtained his PhD in neurobiology at the Rockefeller University in 1983, and his MD from Cornell in 1984. Goldman interned in Medicine and did his residency in Neurology at New York Hospital-Cornell and the Memorial Sloan-Kettering Cancer Center, before joining the Cornell faculty, where he became the Cummings Professor of Neurology before moving to Rochester in 2003 and Copenhagen in 2014. Goldman is interested in cell genesis and regeneration in the adult brain. His lab focuses on the use of patient-derived stem and progenitor cells for the modeling of the neurodegenerative and neuropsychiatric disorders, as well as for the cell-based treatment of myelin diseases. Dr. Goldman was awarded the 2014 Novo Nordisk Foundation Laureate Award, is a recipient of the Jacob Javits Neuroscience Investigator Award of the NIH, and has been elected to Academia Europaea, the Association of American Physicians, the American Society for Clinical Investigation, and American Neurological Association. Goldman is an emeritus chairman of Rochester's Department of Neurology, founding director of its neuro-oncology program, and a former member of the FDA's Cell, Tissue and Gene Therapy Advisory Committee. His work is supported by NINDS, NIMH, the NY Stem Cell Research Board, the Mathers and Adelson Medical Research Foundations, ALS Association, CHDI Foundation, PML Consortium, the Lundbeck and Novo Nordisk Foundations, and NovoSeeds.

Clive Svendsen, PhD

Cedars-Sinai Medical Center

Dr. Svendsen did his pre-doctoral training at Harvard University and received his PhD from the University of Cambridge in England where he then established a stem cell research group before moving to the University of Wisconsin in 2000 to became Professor of Neurology and Anatomy, Director of an NIH funded Stem Cell Training Program and Co-Director of the University of Wisconsin Stem Cell and Regenerative Medicine Center. In 2010 he moved to Los Angeles to establish and direct the Cedars-Sinai Regenerative Medicine Institute which currently has 15 faculty members and approximately 100 staff. One focus of his current research is to derive cells from patients with specific disorders which can then be "reprogrammed" to a primitive state and used as powerful models of human disease. Dr. Svendsen led the first groups to successfully model both spinal muscular atrophy and more recently Huntington's disease using this technology. The other side of his research involves cutting edge clinical trials. He was involved with one of the first growth factor treatments for Parkinson's disease and is currently working closely with neurosurgeons, neurologists and other scientists to develop novel ways of using stem cells modified to release powerful growth factors to treat patients with neurological diseases such as ALS, Huntington's, Alzheimer's and Parkinson's.

David H. Rowitch, MD, PhD, ScD

University of Cambridge, United Kingdom

David Rowitch, MD PhD ScD is Professor and Head of Pediatrics at the University of Cambridge, and he holds a joint appointment at UCSF (Pediatrics and Neurological Surgery). He is a neonatologist and neuroscientist whose laboratory investigates genetic factors that determine development and diversity of glial cells of the brain and the response to injury. He has applied these principles to better understand white matter injury in premature infants, brain cancer and leukodystrophy. Rowitch led the first human clinical trial of direct neural stem cell transplantation focused on the rare and fatal leukodystrophy, Pelizaeus-Merzbacher Disease (PMD).

His work in the field of neurobiology has earned him numerous awards. He became a Howard Hughes Medical Institute Investigator in 2008 and Professor of Pediatrics at Cambridge University and Wellcome Trust Senior Investigator in 2016. His interest in precision medicine focuses on applications of genomic technologies to diagnose and better understand the biological basis and rational treatment of rare neurological disorders.

Session IV: Disease-modifying Therapies that Slow Disease Progression

Session Chair: Michael J. O'Neill, PhD, Eli Lilly and Company

Eric Karran, BSc, PhD

AbbVie

Eric H. Karran PhD is a molecular biochemist by training. He is currently at AbbVie where he is Vice President, Distinguished Research Fellow and Site Head of the Foundational Neuroscience Center in Cambridge, Boston. Previously Eric was the Director of Research for Alzheimer's Research UK. He has held senior positions in a number of companies, including SmithKline Beecham (now GSK), Pfizer, Eli Lilly and at Johnson and Johnson. Eric has specialized in Neuroscience research, particularly Alzheimer's disease and other neurodegenerative diseases, for the past 20 years. Eric is a Visiting Professor in the Department for Human Genetics at the Catholic University of Leuven, Belgium; a Visiting Professor in the Department of Molecular Neuroscience at the Institute of Neurology, University College London; and Visiting Professor of Neurodegenerative Diseases at the University of Lincoln, United Kingdom.

Session V: Innovative Approaches to Modify Neurogenesis and to Promote Neuroregeneration

Session Chair: David Bleakman, PhD, Eli Lilly and Company

Graham Collingridge, FRS, FMedSci, FSB, FBPhS,

University of Toronto, Canada

Dr. Collingridge is the Ernest B. and Leonard B. Smith Chair of the Department of Physiology, University of Toronto and a Senior Investigator at the LTRI. His research focuses on the hippocampus, a brain region that is critical for learning and memory. He studies the roles of proteins in normal hippocampal physiology and how alterations contribute to brain dysfunction. His work is directly relevant to understanding the underlying causes of a wide range of neurodegenerative conditions such as Alzheimer's disease and psychiatric conditions such as depression, schizophrenia and autism.

Guo-li Ming, MD, PhD

University of Pennsylvania

Dr. Guo-li Ming is currently a Professor of Neuroscience at University of Pennsylvania School of Medicine. She received her medical training on Child and Maternal Care from Tongji Medical University in China in 1994 and PhD from University of California, San Diego in 2002. After her postdoctoral training at the Salk Institute for Biological Studies, she became an Assistant Professor at Johns Hopkins University in 2003 and Professor in 2011. The research in her laboratory centers on understanding the molecular mechanisms underlying neuronal development and its dysregulation using mouse systems and patient derived induced pluripotent stem cells. She has received a number of awards, including Charles E. Culpeper Scholarship in Medical Science inn 2003, Alfred P. Sloan Research Fellow in 2005, Young investigator award from Society for Neuroscience in 2012 and A. E. Bennett Research Award in 2014. She is a member of Society for Neuroscience and American College of Neuropsychopharmacology.

Benedikt Berninger, PhD

University Medical Center Johannes Gutenberg University Mainz, Germany

Benedikt studied Biology at the Ludwig Maximilians University Munich and did his PhD on activity-dependent gene regulation of neurotrophins in the lab of Hans Thoenen at the Max Planck Institute of Psychiatry. After a postdoc with Mu-ming Poo at the University of California San Diego where he studied neurotrophin-induced synaptic plasticity, he became a group leader at the Max Planck Institute of Neurobiology and then staff scientist at the Institute of Stem Cell Research at the Helmholtz Center Munich and the Department of Physiological Genomics of the Ludwig Maximilians University Munich, headed by Magdalena Götz. At this time he started to work on glia-to-neuron reprogramming which has been his main topic ever since. In 2012 he became a full professor at the University Medical Center of the Johannes Gutenberg University Mainz, Germany, where he heads the “Laboratory of Adult Neurogenesis and Cellular Reprogramming”.

Amar Sahay, PhD

Massachusetts General Hospital

Dr. Sahay is an Assistant Professor at the Center for Regenerative Medicine and the Department of Psychiatry at Massachusetts General Hospital, Harvard Medical School. He is also principal faculty of the Harvard Stem Cell Institute of Harvard University. The focus of Dr. Sahay's research interests lies in understanding how stem cells in the adult brain may be harnessed to improve cognition and mood and how alterations in neural circuits contribute to the development of psychiatric disorders. The incidence and complexity of mental illnesses and cognitive impairments associated with ageing and Alzheimer's disease underscores the need to develop novel treatments. The mission of the Sahay Lab is to generate fundamental insights into the role of adult hippocampal neurogenesis, the process by which neural stem cells generate dentate granule neurons throughout life, in hippocampal functions in encoding, memory processing and modulation of mood. By integrating cellular, circuit, systems and behavioral interrogation of adult hippocampal neurogenesis, we aspire to rejuvenate and re-engineer hippocampal circuitry to optimize circuit performance and memory processing. We predict that this strategy will impact diseases such as PTSD, Alzheimer's disease and age-related cognitive decline.

Session VI: Hot Topic Talks from Submitted Abstracts

Session Chair: Academy Representative To Be Announced

Johanna Jackson, PhD

Eli Lilly and Company

Milo Robert Smith

Icahn School of Medicine at Mount Sinai

Eliška Zlámalová

University of Cambridge, United Kingdom

Session VII: Biomarkers and Imaging Modalities for Neuroregeneration

Session Chair: David Bleakman, PhD, Eli Lilly and Company

Reisa A. Sperling, MD, MMSc

Brigham and Women's Hospital

Dr. Reisa Sperling is a neurologist specializing in the early detection and treatment of Alzheimer's disease. She is a Professor in Neurology at Harvard Medical School, Director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital, and Director of Neuroimaging for the Massachusetts ADRC at Massachusetts General Hospital. She is the co-Principal Investigator of the Harvard Aging Brain Study, an NIH funded Program Project. Dr. Sperling led the National Institute on Aging-Alzheimer's Association workgroup to develop guidelines for “Preclinical Alzheimer's disease,” and currently serves on the Advisory Council of the NIA. She is the Project Leader for the Anti-Amyloid Treatment in Asymptomatic AD (A4) study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, funded by the Alzheimer's Association. She is also the PI of the recently awarded Ante-Amyloid prevention of AD – the “A3” Study — a new trial that aims to prevent amyloid accumulation in high-risk individuals.

Arthur Konnerth, PhD

Technical University of Munich, Germany

Arthur Konnerth investigates elementary mechanisms of brain function. By using various methods of molecular and cellular analyses in animal models in vivo, including fluorometric imaging techniques (e.g. multiphoton microscopy), he focuses on synaptic interactions in neuronal networks of the healthy and the diseased brain to obtain a better understanding of mechanisms underlying learning and memory formation. Arthur Konnerth studied medicine at the LMU Munich and obtained his doctorate at the Max Planck Institute of Psychiatry in Munich (1983). He is currently the director of the Institute of Neurosciences at TU Munich. He is a member of the German Academy of Sciences Leopoldina, the Academia Europaea and the Bavarian Academy of Sciences and Humanities.

Session VIII: The Future of Research and Therapies in Neuroregeneration and Neurorestoration

Session Chair: Michael J. O'Neill, PhD, Eli Lilly and Company

Ralph A. Nixon, MD, PhD

New York University Langone Medical Center
Professor of Psychiatry and Cell Biology, New York University Langone Medical Center; Director of Research and the Center for Dementia Research, Nathan S. Kline Institute.

Dr. Nixon received his PhD from Harvard University, MD from University of Vermont, and training in medicine and psychiatry at Massachusetts General Hospital. He is a Fellow of the American College of Neuropsychopharmacology. Dr. Nixon's research was the first to establish the importance of proteases and defective proteolytic systems in the pathogenesis of Alzheimer's disease and has identified new therapeutic approaches for the disease. A major focus of his research is on the pathogenic importance of endosomal-lysosomal and autophagy dysfunction in neurodegenerative diseases. This work has revealed presenilins as essential for lysosome function and presenilin mutations, the most common cause of early onset Alzheimer's disease, as key accelerants of the disease through lysosomal mechanisms. He currently directs a multi-institutional NIH supported Program Project on Alzheimer's disease.

He has published over 290 scientific papers and is the holder of nine issued and pending patents. He served as Chairman of the Medical and Scientific Advisory Council (MSAC) of the national Alzheimer's Association and is currently a member of the Association's National Board of Directors. He also serves on the Governor's Commission on Alzheimer's disease for New York State. Dr. Nixon's awards include the Leadership and Excellence in Alzheimer Research, MERIT, and Academic Career Leadership Awards from the National Institutes of Health and the Zenith, Temple Discovery, and Khachaturian Awards from the Alzheimer's Association.

Ana Maria Cuervo, MD, PhD

Albert Einstein College of Medicine

Ana Maria Cuervo is the R.R. Belfer Chair for Neurodegenerative Diseases, Professor in the Departments of Developmental and Molecular Biology and of Medicine of the Albert Einstein College of Medicine and co-director of the Einstein Institute for Aging Studies. She obtained her MD and a PhD in Biochemistry and Molecular biology from the University of Valencia (Spain) and received postdoctoral training at Tufts University, Boston. In 2002, she started her laboratory at the Albert Einstein College of Medicine, where she continues her studies in the role of protein-degradation in neurodegenerative diseases and aging.

Dr. Cuervo has received prestigious awards such as the P. Benson and the Keith Porter in Cell Biology, the Nathan Shock Memorial Lecture, the Vincent Cristofalo and the Bennett J. Cohen in basic aging biology and the Marshall Horwitz and the Saul Korey Prize for excellence in research and in Translational Medicine. She delivered prominent lectures such as the Robert R. Konh, the NIH Director's, the Roy Walford, the Feodor Lynen, the Margaret Pittman, the IUBMB Award, the David H. Murdoxk, the Gerry Aurbach and the Harvey Society Lecture. She is currently co-Editor-in-Chief of Aging Cell and has been member of the NIA Scientific Council and of the NIH Council of Councils.

Mark P. Mattson, PhD

National Institute of Aging, National Institute of Health

After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders-Brown Center on Aging at the University of Kentucky College of Medicine where he advanced to Full Professor. In 2000, Dr. Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine. Dr. Mattson's research is aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. His work has elucidated how the brain responds adaptively to challenges such as fasting and exercise, and he has used that information to develop novel interventions to promote optimal brain function throughout life. Dr. Mattson is among the most highly cited neuroscientists in the world with an ‘h' index of over 190. He has received many awards including the Metropolitan Life Foundation Medical Research Award and the Alzheimer's Association Zenith Award. He was elected an AAAS Fellow in 2011. He is Editor-in-Chief of Ageing Research Reviews and is a Reviewing or Associate Editor for the Journal of Neuroscience, Trends in Neurosciences, the Neurobiology of Aging, and Aging and Mechanisms of Disease.

Clive Svendsen, PhD

Cedars-Sinai Medical Center

Dr. Svendsen did his pre-doctoral training at Harvard University and received his PhD from the University of Cambridge in England where he then established a stem cell research group before moving to the University of Wisconsin in 2000 to became Professor of Neurology and Anatomy, Director of an NIH funded Stem Cell Training Program and Co-Director of the University of Wisconsin Stem Cell and Regenerative Medicine Center. In 2010 he moved to Los Angeles to establish and direct the Cedars-Sinai Regenerative Medicine Institute which currently has 15 faculty members and approximately 100 staff. One focus of his current research is to derive cells from patients with specific disorders which can then be "reprogrammed" to a primitive state and used as powerful models of human disease. Dr. Svendsen led the first groups to successfully model both spinal muscular atrophy and more recently Huntington's disease using this technology. The other side of his research involves cutting edge clinical trials. He was involved with one of the first growth factor treatments for Parkinson's disease and is currently working closely with neurosurgeons, neurologists and other scientists to develop novel ways of using stem cells modified to release powerful growth factors to treat patients with neurological diseases such as ALS, Huntington's, Alzheimer's and Parkinson's.

Jeffrey Macklis, MD, DHST

Harvard University

Macklis is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University, and Professor of Neurology [Neuroscience] at Harvard Medical School, and was founding Program Head, Neuroscience, Harvard Stem Cell Institute. He is an M.I.T. faculty member in the Harvard-Massachusetts Institute of Technology (M.I.T.) Division of Health Sciences and Technology. His lab is directed toward both: 1) understanding molecular controls and mechanisms over neuron sub-type specification, development, diversity, axon guidance-circuit formation, and degeneration in the cerebral cortex; and 2) applying developmental controls toward both brain and spinal cord regeneration and directed differentiation for in vitro therapeutic and mechanistic screening. The lab focuses on neocortical projection neuron development and sub-type specification; neural progenitor / “stem cell” biology; induction of adult cortical neurogenesis; subtype-specific axonal growth cone biology; and directed neuronal subtype differentiation via molecular manipulation of neural progenitors and pluripotent cells (ES/iPS). He is the recipient of a number of awards, including a Rita Allen Foundation Scholar Award, a Director's Innovation Award from the NIH Director's Office, The CNS Foundation Award, a Senator Jacob Javits (MERIT) Award in the Neurosciences from NINDS/NIH, The Cajal-Krieg Cortical Discoverer Prize, and he is an Allen Distinguished Investigator of the Paul G. Allen Family Foundation, and a Brain Research Foundation Fellow.

 

Abstracts

Keynote Address

Astrocytes in Central Nervous System Repair and Regeneration
Michael V. Sofroniew, MD, PhD, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, United States

Astrocytes respond to all forms of central nervous system (CNS) damage. Molecular dissection in vivo shows that astrocyte reactivity is a broad spectrum of potential changes ranging from mild functional changes to overt scar formation. These changes are regulated by heterogeneous molecular signaling mechanisms in a context specific manner. Genetic loss-of-function studies are identifying diverse beneficial functions of reactive astrocytes, for example in regulating CNS inflammation or synaptic reorganization after CNS insults. Other studies indicate that contrary to long-standing dogma, newly-proliferated scarforming astrocytes aid, rather than inhibit, the regeneration of damaged CNS axons. Roles for astrocytes in sustaining and restoring neural circuit function after CNS injuries, including contributions to tissue repair, synaptic plasticity and regeneration are being explored and identified. The potential for astrocyte dysfunction to contribute to neural dysfunction is also being demonstrated. A conceptual framework is emerging that encompasses both ‘normal astrocyte reactivity’ that is critical for preservation of tissue and function after CNS insults, and ‘dysfunctional astrocyte reactivity’ which may be harmful through loss-of-functions due to genetic defects, genetic polymorphisms, autoimmune attack, or chronic exposure to inflammatory stimuli.
 
Anderson et al. (2016) Astrocyte scar formation aids central nervous system axon regeneration. Nature 532:195-200
Sofroniew MV (2015) Astrocyte barriers to neurotoxic inflammation. Nat Rev Neurosci 16:249-63
Burda JE, Sofroniew MV (2014) Reactive gliosis and the multicellular response to CNS damage and disease. Neuron 81:229-248
 

Regulation of Synapses and Synaptic Strength
Richard Tsien, DPhil, New York University School of Medicine, New York, New York, United States

Which brain disorders are truly diseases of the synapse – full blown synaptopathies? If dysfunctional synapses and abnormal excitability contribute, what are the other elements and how do they all knit together? These questions recur in disorders ranging from Alzheimer’s to autism. Here we address such generic issues in a specific case, by reporting our studies of autism spectrum disorder (ASD), a monogenic, dominant form called Timothy Syndrome (TiS). Individuals with TiS develop ASD with a >60% likelihood because of a point mutation in the pore-forming subunit of a calcium channel (CACNA1C, encoding CaV1.2). In a mouse model (TS2-neo), we found persistent and repetitive behavior, reduced social interaction, and altered vocalizations, impetus for clarifying the pathophysiology. Dysfunctional homeostatic plasticity is often suggested as a possible pathogenic mechanism for ASD. In studying homeostatic adaptation, we discovered intriguing differences in the autoregulation of synaptic weights and intrinsic excitability in TS2-neo cortical pyramidal cells subjected to action potential blockade by 24 hour tetrodotoxin (TTX) treatment. TS2-neo pyramidal neurons exhibited an exaggerated upregulation in amplitude and frequency of unitary events, accompanied by higher intensity of GluA1-containing AMPA receptors. Homeostatic adaptation of intrinsic excitability was similarly exaggerated. We observed similar electrophysiological alterations in layer 2/3 pyramidal neurons in primary visual cortex recorded ex vivo from visually deprived WT and TS2 animals. These results fit with notion that homeostatic autoregulatory effects can be abnormally large in ASD. They also provide novel perspective on how CaV1.2 operates as an activity reporter.
 
Coauthors: Simon D. Sun, BS, Ben S. Suutari, BS, Boxing Li, PhD
New York University School of Medicine, New York, New York, United States
 

Striatal Plasticity in Parkinson's Disease
D. James Surmeier, PhD, Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the United States. The core motor symptoms of PD are a consequence of the degeneration of dopaminergic neurons that innervate the striatum. This innervation not only modulates the short-term excitability of striatal neurons but also shapes the strength of corticostriatal synapses in a way that regulates goal-directed and habitual actions. The loss of this innervation leads to an imbalance in the excitability of striatal circuits modulating basal ganglia circuits, leading to the hypokinetic features of the disease. It is widely appreciated that the striatal imbalance stems from the differential expression of dopamine receptors by direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs). What is less appreciated is the extent to which intrinsic and synaptic homeostatic plasticity, particularly in iSPNs, mitigate the consequences of declining dopaminergic signaling, but distort striatal connectivity with the cerebral cortex. Symptomatic therapies that restore basal levels of dopamine in the striatum can reverse alterations in intrinsic excitability but fail to correct distortions in synaptic strength. Moreover, with fluctuations in striatal dopamine levels, aberrant synaptic plasticity leads to the motor complications or dyskinesia. The presentation will summarize recent work in mouse models of PD exploring these adaptations in the striatal circuitry and strategies for reducing their impact on symptom severity.
 
Coauthors: Asami Tanimura, PhD, Steven M. Graves, PhD, and Weixing Shen, PhD, Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
 

Novel Mechanisms of Immune-mediated Nervous System Regeneration
Roman J. Giger, PhD, University of Michigan School of Medicine, Ann Arbor, Michigan, United States

Innate immunity can facilitate nervous system regeneration, yet the underlying cellular and molecular mechanisms are not well understood. We found that intraocular injection of lipopolysaccharide (LPS), a bacterial cell wall component, or the fungal cell wall extract zymosan both lead to rapid and comparable intravitreal accumulation of blood-derived myeloid cells. However, when combined with retro-orbital optic nerve crush injury, lengthy growth of severed retinal ganglion cell (RGC) axons occurs only in zymosan-injected mice, and not in LPS-injected mice. In mice deficient for the pattern recognition receptor dectin- 1 but not Toll-like receptor-2 (TLR2), zymosan-mediated RGC regeneration is greatly reduced. The combined loss of dectin-1 and TLR2 completely blocks the pro-regenerative effects of zymosan. In the retina, dectin-1 is expressed by microglia and dendritic cells, but not by RGCs. Dectin-1 is also present on blood-derived myeloid cells that accumulate in the vitreous. Intraocular injection of the dectin-1 ligand curdlan [a particulate form of β(1, 3)-glucan] promotes optic nerve regeneration comparable to zymosan in WT mice, but not in dectin-1(-/-) mice. Particulate β(1, 3)-glucan leads to increased Erk1/2 MAP-kinase signaling and cAMP response element-binding protein (CREB) activation in myeloid cells in vivo. Loss of the dectin-1 downstream effector caspase recruitment domain 9 (CARD9) blocks CREB activation and attenuates the axon-regenerative effects of β(1, 3)-glucan. Studies with dectin-1(-/-)/WT reciprocal bone marrow chimeric mice revealed a requirement for dectin-1 in both retina-resident immune cells and bone marrow-derived cells for β(1, 3)-glucan-elicited optic nerve regeneration. Collectively, these studies identify a molecular framework of how innate immunity enables repair of injured central nervous system neurons.
 

Subtype-specific Local Growth Cone Control over Circuit Development, Regeneration, and Degeneration
Jeffrey D. Macklis, MD, DHST, Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University, Cambridge, Massachusetts, United States

The formation of circuits throughout the nervous system, and within and from the cerebral cortex in particular in this presentation, relies heavily on molecular machinery localized at the tips of growing axons in structures termed growth cones (GCs). Subsets of neurons’ transcriptomes and proteomes localize to GCs to implement growth and guidance of nascent axons toward their specific targets. Until now, these subcellular and likely subtypespecific RNA and protein networks have not been experimentally accessible directly from the brain. Here, I will report subtype-specific GC sorting and subcellular RNA-Proteome mapping as a generalizable approach to reveal and investigate local molecular machinery that drives brain circuit development. Applying this approach to the long-range axon projections of callosal projection neurons connecting the two hemispheres of the cerebral cortex, and to corticothalamic projection neurons, we identify that native GCs 1) possess remarkably deep and rich molecular constituents for local synthesis, folding, and turnover of select protein classes, suggesting function as "mini-cellular" and significantly ~autonomous units; 2) that each subtype contains both quite distinct, subtype-specific molecular machinery plus shared molecular machinery; 3) that hundreds of proteins and hundreds of RNAs (coding and not) are enriched orders of magnitude in GCs compared to their own parent somata, indicating subcellular polarity and isolation of functions; 4) that targeting motifs direct subtype-specific GC localization. As one example, we identify a hub molecule regulating cell growth found specifically in axon GCs rather than cell bodies, and that mRNA classes distribute within developing projection neurons based on their sensitivity for translation. Essentially this entire class of transcripts map specifically to GCs and not to their parent cell bodies. Given the importance of growth control for axon growth and regeneration, this subcellular organization might also have implications for future regenerative strategies in the nervous system. Subtype-specific GC sorting and differential subcellular RNA-proteome mapping is applicable to any labeled neurons in the nervous system, enabling identification of specific molecular substrates of circuit development, regeneration, and mis-wiring causing neuronal circuit pathology. The ability to directly compare multiple distinct GC-soma subtypes using multi-color sorting makes this approach broadly applicable to future studies in the fields of axon guidance, neurodevelopmental disorders, and neuron reprogramming. Subcellular RNA-proteome mapping enables identification of distinguishing molecular constituents of subtype-specific GCs with complex and unique trajectories that ultimately target distinct brain areas. Further, it enables direct molecular investigation of subtype-specific GCs compared with GCs from mutant, regenerative, non-regenerative, or reprogrammed neurons to discover molecular mechanisms of circuit development, mis-wiring, and regeneration.
 

Intermittent Bioenergetic Challenges Bolster Brain Resilience
Mark P. Mattson, PhD (1,2)
(1) Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland, United States
(2) Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States

Evolutionary considerations suggest that the brain should function well/optimally during periods of food deprivation/fasting and physical exertion. Brain-intrinsic pathways and peripheral signals by which fasting and exercise promote synaptic plasticity, neurogenesis and resilience under stressful conditions are being elucidated. Our findings suggest that running and fasting can stimulate mitochondrial biogenesis in neurons by mechanisms involving BDNF signaling and PGC-1α, a pathway critical for the formation and maintenance of synapses. The mitochondrial protein deacetylase SIRT3 mediates adaptive responses (stress resistance and modulation of neuronal network activity) of neurons to exercise and fasting. By mechanisms involving deacetylating SOD2 and cyclophilin D, SIRT3 protects neurons in animal models of acute brain injury and neurodegenerative disorders. Interestingly, behavioral adaptations to intermittent fasting (reduced anxiety and preservation of cognitive performance) involve SIRT3-dependent enhancement of GABAergic tone in the hippocampus, which may also protect against excitotoxicity. Regarding peripheral signals generated in response to fasting and vigorous exercise, we found that the ketone -hydroxybutyrate, which is produced from fatty acids during fasting and vigorous exercise, can stimulate BDNF production, which may mediate beneficial effects of these bioenergetic challenges on neuronal plasticity and stress resistance. Additional data suggest that combining energy restriction with exercise can elicit additive or synergistic beneficial effects on neuroplasticity and performance. Collectively, the emerging picture of bioenergetics and brain health reveals that intermittent energy restriction and exercise promote neuroplasticity and resistance to injury and disease, whereas a ‘couch potato’ lifestyle fosters suboptimal brain function and poor resilience. Supported by the NIA Intramural Research Program.
 

Malfunctioning Autophagy and its Pathway to Neurodegeneration
Ana Maria Cuervo, MD, PhD, Albert Einstein College of Medicine, Bronx, New York, United States

Autophagy is an essential cellular process that contributes to cellular quality control and to maintenance of the cellular energetic balance. Failure of different types of autophagy in neurons has been shown to result in major alterations in neuronal proteostasis, energetics and functioning and have been linked to severe neurodegenerative disorders. We have identified a dynamic cross-talk among different forms of autophagy that is used to protect cells from failure in any of these systems and to avoid toxic effects of pathogenic proteins on them. To gain a better understanding of the consequences of autophagy malfunctioning in neurons and on the rules that govern the autophagic cross-talk we have developed a series of mouse models with systemic or tissue-specific blockage of a selective form of autophagy known as chaperone-mediated autophagy (CMA). Analysis of these models has revealed that added to the previously known role of CMA as part of the cellular response to stress, this type of autophagy is also required in the regulation of important cellular processes such as metabolism of lipids and carbohydrates, cell cycle, cell reprograming and cellular differentiation. Phenotypic characterization of these mice is allowing us to link CMA deficiency with different age-related neurodegenerative diseases.
 

Mitochondrial-linked Mechanisms and Therapeutic Opportunities
Valina L. Dawson, PhD (1,2)
(1) Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Departments of Physiology, Neurology and the Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
(2) Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, United States

Parkinson's disease (PD) is a common neurodegenerative disease of complex etiology with roughly 90% of PD cases considered sporadic, and 10% attributable to familial mutations. Mutations in the parkin gene, which encodes the E3 ligase parkin, are the most common cause of autosomal recessive PD. To date, more than 100 pathogenic parkin mutations disrupt the protein's E3 ligase activity, either directly or by altering the solubility or stability of the protein, leading to dopaminergic cell death. Importantly, recent evidence from post-mortem PD brain samples and mouse models suggest that parkin is inactivated by post-translational modifications, including oxidation, nitrosylation, addition of dopamine and phosphorylation by c-Abl, an important stress-activated non-receptor tyrosine kinase that is activated in sporadic PD brains and in animal models of PD. Thus, inactivation of parkin maybe a common and critical feature of PD. PARIS (ZNF746) is a pathologic parkin substrate, which contributes to DA neuronal loss in animal models of parkin inactivation. PARIS accumulation plays a repressive function against the transcriptional coactivator, peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) expression, thought to be critical for DA neuron survival. Consistent with its role in DA neuronal toxicity, PARIS accumulates in mouse brain with parkin inactivation and importantly in human sporadic and familial PD brains. Dysfunction of parkin has profound effects on mitochondrial quality control (autophagy, transport, fusion, fission and biogenesis), with PARIS playing an important role in mediating parkin’s effect in biogenesis. Disruption of the homeostatic mechanisms that controls the content of mitochondria in a cell through degradation (mitophagy) and synthesis (biogenesis), can lead to neurodegeneration and significantly contribute to the pathogenesis of PD.
 

Human Glial Progenitor Cell-based Treatment and Modeling of Neurological Disease
Steven A. Goldman, MD, PhD (1,2)
(1) University of Copenhagen Faculty of Medicine, Copenhagen, Denmark
(2) University of Rochester Medical Center, Rochester, New York, United States

The most abundant precursor cells of the adult human brain are glial progenitor cells (GPCs), which can give rise to both astrocytes and oligodendrocytes. As a result, diseases of glia may provide readily accessible targets for cell-based therapies. The glial diseases, which include the myelin disorders as well as those referable to astrocytic dysfunction, are among the most prevalent and disabling conditions in neurology, and may be particularly appropriate targets for progenitor cell-based therapy. This talk will focus on the potential utility of transplanting pluripotent stem cell-derived GPCs as a means of treating the diseases of myelin, as well as of those neurodegenerative disorders with significant astroglial involvement. I will also discuss the utility of the glial chimeric mice that result from the neonatal implantation of human GPCs into the mouse brain. In these mice, the human glial progenitors out-compete their murine counterparts to eventually dominate the glial population of the recipient brains. Human glial chimerization has significant effects on neurophysiology and behavior, which suggest the importance of human-specific glial attributes to neural network function. By generating human glial chimeric mice using patient-derived hiPSC-derived GPCs, we may now investigate the causal contributions of glia to human brain disease, by producing disease-specific human glial chimeras. These mice provide us a new model system by which to study not only the myelin disorders, but the entire range of neurodegenerative and neuropsychiatric diseases in which glia may causally participate.
 

Stem Cell-derived Astrocytes for the Treatment Neurodegenerative Diseases
Clive Svendsen, PhD, Cedars-Sinai Medical Center, Los Angeles, California, United States

Astrocytes and growth factors play a key role in brain health and functioning. We have developed a reliable way of expanding human neural progenitors from both fetal tissue and iPSCs as organoids without losing cell/cell contact. These organoids transition from making neurons to astrocytes at around passage 20. They can also be genetically modified to release powerful growth factors such as GDNF. We have been developing translational approaches to use these cells for treating amyotrophic lateral sclerosis (ALS), parkinson's disease (PD), huntington's disease (HD), alzheimer’s disease (AD), and retinal diseases. For ALS we have initiated a Phase 1/2a clinical trial in 18 patients to establish whether this approach can slow degeneration and maintain function.
 

Development of Functionally Heterogeneous Astrocytes in Mammalian Central Nervous System
David H Rowitch (1,2)

Astrocytes are heterogeneous in terms of morphology, gene expression and physiological properties. How is such diversity determined? This talk will focus on advances in understanding astrocyte development including the role of neural tube patterning in specification and developmental functions of astrocytes during synaptogenesis, axon path finding and motor neuron survival. We propose that a precise understanding of astrocyte development is critical to defining heterogeneity and could lead to a better appreciation for their roles in support of local-regional neural circuits. For example, we have shown that ventral spinal cord astrocytes express Sema3a, which is essential for synaptogenesis and motor neuron survival. New screening approaches could indicate diversification of cortical astrocytes conferring layer-specific functions. Such information leads to the proposal that optimized cell-based neuronal therapies would be augmented by co-transplant of regional specialized astrocytes.
 
Coauthors: Omer Bayrakartar (1,2), Anna V Molofsky (2), Kevin W. Kelley (2), Hui Hsin Tsai (2), Huiliang Li (3), Raquel Taveira Marques (3), Helin Zhuang (3), Arturo Alvarez-Buylla (2), Robert Krencick (2), Erik M Ullian (2), Nicola Allen (4), William D Richardson (3)
(1) University of Cambridge, Cambridge, United Kingdom
(2) University of California, San Francisco, San Francisco, California, United States
(3) University College London, London, United Kingdom
(4) Salk Institute, La Jolla, California, United States

 

Industry Perspective Lecture

Disease-modifying Drugs for Alzheimer's Disease — The Past and The Future
Eric Karran, BSc, PhD, Foundational Neuroscience Center, AbbVie, Cambridge, Masschusetts, United States

Alzheimer’s disease is a devastating neurodegenerative disease that follows an unremitting course leading to severe cognitive impairment. Increasing age represents the greatest risk factor and as the population shifts to an increasingly elderly demographic, the incidence and prevalence of this disorder will likely increase. No therapies are available that slow or prevent the progression of the disease, and recently, promising agents have failed in phase 3 clinical testing. I will review previous clinical trials to determine what might be learned, and consider what future trials may reveal.
 

Is Alzheimer's Disease Caused by Long-term Depression Gone Awry?
Graham Collingridge, FRS, FMedSci, FSB, FBPhS (1,2,3)
(1) Department of Physiology, University of Toronto, Toronto, Canada
(2) Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
(3) School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, United Kingdom

There is growing evidence that dysregulated synaptic plasticity is a contributing factor in a wide variety of neurological and psychiatric disorders. We have proposed that one form of synaptic plasticity, N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD), becomes overactive and triggers synapse elimination and the associated cognitive deficits in neurodegenerative conditions, such as Alzheimer’s disease. NMDAR-LTD is particularly prevalent early in development where it is likely to be involved in the physiological pruning of superfluous synaptic connections. It is then largely down regulated. We propose that a variety of genetic and environmental factors may lead to the inappropriate reactivation of NMDAR-LTD and that this constitutes an early and causal element in neurodegenerative conditions. In support of this hypothesis, we have found that a variety of molecules that are closely associated with Alzheimer's disease are integral components of the LTD process. Such a mechanism can explain the link between Abeta and tau and can, in theory, underlie both Abeta-dependent and Abeta-independent forms of neurodegenerative disorders.
 

Modeling Human Brain Development and Disorders using Human Induced Pluripotent Stem Cells (hiPSCs)
Guo-li Ming, MD, PhD, Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania

Three dimensional (3D) cerebral organoid cultures from human iPSCs have been recently developed to recapitulate the cytoarchitecture of the developing brain. This system offers unique advantages in understanding molecular and cellular mechanisms governing embryonic neural development and in modeling congenital neurodevelopmental disorders, such as microcephaly. We have improved the organoid technology and developed a robust protocol to produce forebrain-specific organoids derived from human iPSCs using a novel miniaturized spinning bioreactor that recapitulate the human embryonic cortical development. ZIKV, a mosquito-borne flavivirus, has re-emerged as a major public health concern globally because ZIKV causes congenital defects, including microcephaly, and is also associated with Guillain-Barré syndrome in infected adults. We found that ZIKV exhibit specific tropism towards human neural progenitor cells and results in cell death and defects in neural development. I will discuss our recent work in further dissecting the molecular mechanisms underlying the ZIKV pathogenesis and microcephaly.
 

Engineering of Neurogenesis via Lineage Reprogramming
Benedikt Berninger, PhD (1)

Engineering new neurons via lineage reprogramming provides new avenues for brain repair. We have previously found that reprogramming of glia into induced neurons in the adult mouse cerebral cortex was dependent on prior injury. One of the hallmarks of the injury response is increased glial proliferation. We reasoned that if proliferation is a property conducive for lineage conversion that glial populations that undergo expansive cell division during postnatal brain development may be endowed with a greater reprogramming competence. Indeed we found that forced expression of Ascl1 and Sox2 (AS) or Neurog2 and Bcl2 (NB) resulted in the generation of neurons in the absence of a prior injury. Interestingly NB- and AS-induced neurons differed markedly in their physiological properties, with the former developing in more mature neurons in terms of morphology and physiology. Choice of reprogramming factors is likely to impact the conversion trajectory. Using single cell RNA-sequencing we found that AS-induced reprogramming of adult human brain pericytes into induced GABA-positive neurons is not accomplished via immediate replacement of the pericyte transcriptional program by a terminal neuronal program, but involves the transition through a interneuron precursor-like state, albeit in the absence of cell division. Intriguingly, successful induction of the precursor state depends on the synergism between the two transcription factors as either factor alone results in the induction of gene expression profiles that markedly diverge from that induced when expressed conjointly. Our data reveal part of the molecular logic that drives lineage conversion of non-neural cells towards a GABA neuron identity.
 
Coauthors: Marisa Karow, PhD (1,2), Sophie Péron, PhD (1), Nicolás Marichal, PhD (1), Sven Falk, PhD (2), Gray Camp, PhD (3), Barbara Treutlein, PhD (3)
(1) University Medical Center Mainz of the Johannes Gutenberg University Mainz, Mainz, Germany
(2) Biomedical Center Munich, Ludwig-Maximilians University of Munich, Munich, Germany
(3) Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany

 

Rejuvenating and Re-engineering Aging Memory Circuits
Amar Sahay, PhD (1,2,3,4)
(1) Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States
(2) Harvard Stem Cell Institute, Cambridge, Massachusetts, United States
(3) Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
(4) BROAD Institute of Harvard and MIT, Cambridge, Massachusetts, United States

Episodic memory impairments and loss of memory precision are hallmarks of age-related cognitive decline and mild cognitive impairment (MCI). Studies by us and others have implicated adult hippocampal neurogenesis in resolution of memory interference through population based coding mechanisms that support pattern separation. Here, I will present two complimentary approaches, modulation of neuronal competition dynamics and molecular control of granule cell recruitment of inhibition, by which we can rejuvenate and re-engineer the dentate gyrus-CA3 circuit to improve memory precision in adulthood and aging.
 

In Vivo Two-photon Imaging of the Effects of Tauopathy and Amyloidopathy on Synapse Dynamics
Johanna Jackson (1)

A progressive loss of synapses occurs at the early clinical stages of Alzheimer’s disease (AD) and has been correlated with cognitive deficits in patients. However, it is relatively unknown how synapse dynamics are affected by the two main pathological hallmarks of AD; the accumulation of tau and beta-amyloid. Here we used in vivo two-photon microscopy to assess the temporal dynamics of axonal boutons and dendritic spines in mouse models of human tauopathy (rTg4510) and amyloidopathy (J20). Following a craniotomy, adeno-associated virus expressing green fluorescent protein was injected into the somatosensory cortex to enable the visualisation of neurons and a cranial window was implanted for long-term imaging. GFP-labelled neurons were imaged in both models during a time period which spanned the onset of pathology. The gross morphology of neurites and the dynamics of their synaptic structures were assessed as the pathology progressed. In rTg4510s, gross morphological changes such as the presence of dystrophic neurites were visible as the tauopathy progressed and these were found to have a distinctive morphological phenotype prior to neurite degeneration. Alongside this, synapse instability and loss were also observed and could be prevented by suppressing the P301L transgene. In J20 animals, amyloid plaques increased in size and density over time and, whilst spine density was unaffected, spine turnover was increased in the transgenic animals. Both tauopathy and amyloidopathy had effects on synapse dynamics as the respective pathology progressed. These results will inform subsequent drug discovery studies to identify novel therapies to stabilize synapses in AD.
 
Coauthors: Francesco Tamagnini(2), James Johnson (1,3), Terri-Leigh Stephen (1), Zeshan Ahmed (1), Alice Oliver-Evans (1), Soraya Meftah (1), Michael L. Hutton (1), John T. Isaac (1), Andrew Randall (2), Michael C. Ashby (3), and Michael J. O’Neill (1) (1) Lilly UK, Surrey, United Kingdom
(2) University of Exeter, Exeter, United Kingdom
(3) University of Bristol, Bristol, United Kingdom

 

Integrative Bioinformatics Approach to Understand the Role of Plasticity in Neurodegenerative Disease
Milo Robert Smith, Icahn School of Medicine at Mount Sinai, New York, New York, United States

Neuroplasticity is essential to normal brain function throughout life. Identifying brain diseases wherein neuroplasticity is disrupted will uncover novel disease pathophysiology and identify therapeutic targets. Using the well-characterized ocular dominance model of experience-dependent cortical plasticity, we generated transcriptional signatures of plasticity, which we matched to 436 disease signatures using a molecular matching algorithm. We identified diverse diseases associated to plasticity, and implementing a novel Disease Leverage Analysis, found inflammatory pathways as a putative common pathology to suppress experience-dependent plasticity, which we validated in vivo using the lipopolysaccharide model of inflammation (Smith, eNeuro 2016). Inflammation is a hallmark biological pathway common to all neurodegenerative diseases. Consistent with a relationship between plasticity and inflammation, we identified a range of neurodegenerative diseases as strongly associated with plasticity signatures, including Alzheimer's disease, Huntington's disease (HD), Parkinson's disease, and Amyotrophic Lateral Sclerosis, suggesting that experience-dependent plasticity may be disrupted in neurodegeneration. Interestingly, the expression patterns of genes in neurodegenerative disease signatures were heterogeneously correlated with plasticity signatures; independent signatures of the same disease (e.g. HD) indicated both anti-correlated and correlated expression patterns. Given that pre-symptomatic HD individuals have heightened plasticity-dependent perceptual learning (Beste, Current Biology 2012), the finding that HD has both correlated and anti-correlated expression relative to plasticity suggests a dynamic transcriptional landscape across the natural history of the disease. These findings call for additional work to fully elucidate the transcriptional trajectory of HD and other neurodegenerative diseases to facilitate discovery of the right treatment at the right time to restore plasticity and cognition.
 
Coauthors: Joel T. Dudley, PhD, and Hirofumi Morishita, MD, PhD
Icahn School of Medicine at Mount Sinai, New York, New York, United States
 

Testing Hereditary Spastic Paraplegia Genes for Roles in Modeling Axonal Endoplasmic Reticulum in Drosophila
Eliška Zlámalová, University of Cambridge, Department of Genetics, Cambridge, United Kingdom

The hereditary spastic paraplegias (HSPs) are a group of currently untreatable inherited neurologic disorders exhibiting progressively increasing spasticity and weakness of the lower limbs. The prevalence ranges from 3 to 18 in 100,000; hence, there are hundreds of thousands of HSPs sufferers worldwide. The diseases are accompanied by degeneration of corticospinal upper motor neuron axons, which are among the longest in the body. The cellular pathways responsible for causing HSPs are not fully described. The incomplete understanding of mechanisms of axonopathy poses a bottleneck in developing treatments for HSP and related neurodegenerative disorders. Moreover, the known genetic bases for the HSPs can be used to probe basic biological questions of axon formation and maintenance. Some of the most commonly mutated HSP genes encode proteins that model endoplasmic reticulum (ER), suggesting that ER is essential for axon formation and maintenance, and is potentially a location for HSP pathology. We have found that loss of reticulon and REEP proteins in Drosophila results in fewer and larger axonal ER tubules, with occasional gaps in an otherwise continuous axonal ER network. Nevertheless, ER remains present throughout the axon in these mutants, implying that additional proteins help shaping it. Therefore, my aim is to identify other ER-shaping proteins, particularly among HSP gene products, that play roles in axonal ER morphology and function. My strategy involves a small RNAi-based and null mutationbased screen of Drosophila HSP gene orthologs, and combination of confocal and electron microscopy of axonal ER in intact Drosophila knockdown and knockout animals.
 
Coauthors: Belgin Yalçın PhD, Lu Zhao PhD, and Cahir J. O’Kane PhD University of Cambridge, Department of Genetics, Cambridge, United Kingdom
 

Neuroimaging Studies for the Early Detection of Alzheimer's Disease
Reisa Sperling, MD, MMSc (1,2)

One of the continued dilemmas in the field is how best to identify individuals who are clearly on the Alzheimer’s disease (AD) trajectory but at an early enough stage of the AD pathophysiologic process to be maximally responsive to disease-modifying therapies. Converging data from Amyloid PET imaging, cerebrospinal fluid studies and large autopsy series suggest that one-third of clinically normal older individuals harbor a substantial burden of cerebral amyloid-beta (Aß). Accumulating evidence from these “Aß-positive normals” show aberrant functional network activity, cortical thinning and hippocampal atrophy, increased neocortical tau on Tau PET imaging, and other “AD-like” abnormalities on multi-modality imaging. Clinical studies have demonstrated an association between Aß burden and memory performance, greater subjective cognitive concerns, and an increased risk of cognitive decline, particularly among older individuals with markers of both Aß accumulation and neurodegeneration. Recent Amyloid and Tau data acquired in clinically normal older individuals from the Harvard Aging Brain Study and the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study demonstrate a strong relationship between levels of Aß and Tau deposition, as well as an association with memory performance, even prior to clinical symptoms. While Amyloid PET is now increasingly being utilized to select participants for clinical trials in both preclinical (asymptomatic) and clinical (symptomatic) AD populations, Tau PET has particular potential to serve as a theragnostic biomarker outcome.
 
Coauthor: Keith Johnson, MD (2)
(1) Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
(2) Harvard Aging Brain Study, Departments of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States

 

Neuronal Dysfunction in Mouse Models of Alzheimer's Disease In Vivo
Arthur Konnerth, PhD, Technical University of Munich, Munich, Germany

The focus of our research is a better understanding of the impairments of neuronal function in Alzheimer’s disease (AD). Because such analyses of single brain cells are not feasible in patients with AD, we perform most of our experimental work in appropriate mouse models of the disease. An essential feature of AD is the accumulation of amyloid-b (Ab) peptides in the brain, many years to decades before the onset of overt cognitive symptoms. Our results, involving in vivo two photon calcium imaging, suggest that during this very extended early phase of the disease, soluble Ab oligomers and amyloid plaques alter the function of a fraction of brain neurons and consequently that of large-scale networks by disrupting the balance of synaptic excitation and inhibition (E/I balance) in the brain. The analysis of mouse models of AD revealed that an Ab-induced change of the E/I balance caused hyperactivity in cortical and hippocampal neurons, a breakdown of slow-wave oscillations, as well as network hypersynchrony. Remarkably, hyperactivity of hippocampal neurons precedes amyloid plaque formation, suggesting that hyperactivity is one of the earliest dysfunctions in the pathophysiological cascade initiated by abnormal Ab accumulation. Therapeutics that repair the E/I balance in early AD may prevent neuronal dysfunction, widespread cell loss, and cognitive impairments associated with later stages of the disease.
 

The Ups and Downs of Translational Research in Alzheimer's Disease

Ralph A. Nixon, MD, PhD (1,2)
(1) Center of Dementia, Nathan S. Kline Institute, Orangeburg, New York, United States
(2) Departments of Psychiatry and Cell Biology, New York University Langone Medical Center, New York, New York, United States

When discovered, the amyloid precursor protein and its varied cleaved derivatives were initially investigated as modulators of cell growth, homeostasis, and intercellular communication and were viewed as contributors to a multifactorial disease process involving aging, repair, protective, and toxic influences. As AD research shifted strongly toward a paradigm of abeta neurotoxicity, the disease relevance and therapeutic promise of new findings were viewed mainly through the narrow lens of how abeta/ß-amyloid levels were affected. More recently, however, uncertainty as to which of the many multimeric forms of abeta, if any, is a critical driving factor in AD, combined with the less than hoped for results of anti-amyloid clinical trials, has encouraged a return to the multifactorial perspective of AD initiation and progression. Further fueling this return are the varied physiological roles now being identified for causative and risk genes and evidence that perturbations of these genes have disease-related impact well beyond that attributable to abeta. Increasingly, disruptions of processes linked to AD pathogenesis are being recognized in other neurodegenerative diseases of aging suggesting certain shared degenerative mechanisms and therapeutic targets. Strong genetic evidence, for example, implicates disruptions of proteostasis and endolysosomal trafficking and signaling as primary causes of proteinopathy, synaptic dysfunction, and degeneration irrespective of roles played by a particular proteotoxin. The final panel of this meeting will consider how anomalies known in AD and related disorders, such as inflammation, lipid handling/signaling, mitochondrial function, cell cycle, calcium dysregulation, etc – can be integrated into a more comprehensive notion of pathogenesis to yield more predictive disease models and efficacious therapies.