Neuroscience and Immunology

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Neuroscience and Immunology

Tuesday, October 26, 2010

The New York Academy of Sciences

The disciplines of neuroscience and immunology have made substantial scientific achievements, yet the two rarely find a common language and purpose necessary to support scientific breakthroughs. Coming from the study of a variety of seemingly disparate diseases, elements that were previously considered to be domains of one discipline are now discovered in the other (for example, synapses made by T-cells, and cytokines as neuromodulators).

This symposium provides an introduction to the interdisciplinary field of neuroimmunology and presents a compelling case for the role of specific inflammatory cytokines in sickness behavior and clinical depression. Additional topics include how cytokines mediate the stress response at molecular, cellular and systems levels, the molecular mechanisms of cellular stress in Alzheimer's disease and how proinflammatory signaling plays a role in amyloid-beta peptide mediated neuronal dysfunction and memory impairment. Research will be presented that identifies the neurotoxic mechanisms and transduction pathways that are associated with TNFa signaling and potential therapeutic strategies for neurodegenerative diseases via modulating glial reactivity and inflammatory cytokines, and recent discoveries will be unveiled on specific receptors for fibrinogen that advance our understanding of its role from clotting factor to regulator of inflammation.

This event will also be broadcast as a webinar

Please note:
Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

 

Agenda

*Presentation times are subject to change.


Tuesday, October 26, 2010

1:00 PM

Introduction
Ken Jones, PhD, Lundbeck Research USA

1:05 PM

Inflammation and its Discontents: The Role of Inflammation in the Pathophysiology and Treatment of Depression
Andrew H. Miller, MD, Emory University School of Medicine

1:50 PM

The Role of Inflammatory Cytokines in Behavioral and Neural Plasticity
Raz Yirmiya, PhD, Hebrew University

2:30 PM

Role of Proinflammatory Signaling in Neuronal Dysfunction in Alzheimer's Disease: RAGE Molecules and their Potential Impact
Shi Du Yan, MD, MS, Columbia University

3:10 PM

Coffee break

3:35 PM

Role and Regulation of TNF-dependent Neuroinflammation in Models of Neurodegeneration
Malú Tansey, PhD, Emory University School of Medicine

4:15 PM

Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation: Lessons from Multiple Sclerosis
Katerina Akassoglou, PhD, Gladstone Institute & UCSF

4:55 PM

Closing remarks
Seongeun (Julia) Cho, PhD, Food and Drug Administration

Speakers

Organizers

Seongeun (Julia) Cho , PhD

Food and Drug Administration

Ken Jones, PhD

Lundbeck Research USA

Lars Pedersen, PhD

Lundbeck Research USA

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Katerina Akassoglou, PhD

Gladstone Institute & UCSF

Katerina Akassoglou, Ph.D. performed her graduate studies at the University of Athens in Greece and the University of Vienna in Austria, where she developed a novel transgenic animal model for multiple sclerosis. As a recipient of the Human Frontier Science Program (HFSP) postdoctoral fellowship Katerina performed her postdoctoral studies at SUNY at Stony Brook and the Rockefeller University. Following research associate positions at Rockefeller University and New York University, she became assistant professor of pharmacology at the University of California, San Diego in 2003. Since 2008, she is an associate professor of neurology at the University of California, San Francisco and an associate investigator at the Gladstone Institute of Neurologic Disease. Her lab studies molecular mechanisms triggered by vascular damage to induce inflammation and inhibit tissue repair. Her research on interactions of the blood protein fibrinogen with the nervous system identified fibrinogen as a potential therapeutic target in multiple sclerosis. For her work on fibrin and fibrinogen and their role in various neuropathological states, she was recognized by the White House as a recipient of the 2006 Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor bestowed by the United States government on outstanding scientists and engineers beginning their independent careers, and the 2008 John J. Abel Award, given by ASPET and Eli Lilly & Co to a single young investigator for original, outstanding research contributions in the field of pharmacology.

Andrew H. Miller, MD

Emory University School of Medicine

Dr. Andrew Miller is William P. Timmie Professor of Psychiatry and Behavioral Sciences and Director of Psychiatric Oncology at the Winship Cancer Institute at the Emory University School of Medicine in Atlanta, Georgia. Dr. Miller attended medical school at the Medical College of Georgia and did a residency in psychiatry at the Albert Einstein College of Medicine. As a junior faculty member, Dr. Miller trained at Mount Sinai School of Medicine and Rockefeller University in New York. Dr. Miller’s work focuses on the impact of inflammation on behavior and health. He is also interested in the role of glucocorticoid hormones in the regulation of inflammatory responses. Dr. Miller has produced over 200 scholarly publications and edited a book entitled Depressive Disorders and Immunity. Dr. Miller currently has several studies funded by the National Institute of Mental Health and the Centers for Disease Control and Prevention to examine the mechanism and treatment of cytokine-induced depression and fatigue as represented by the cytokine, interferon alpha, which is used for the treatment of infectious diseases and cancer. His interferon alpha studies provide a model to understand and treat depression, fatigue and cognitive dysfunction in medically ill patients including patients with cancer and chronic fatigue syndrome. More recently, Dr. Miller and his group have begun experimenting with the use of cytokine antagonists for patients with treatment resistant depression. Dr. Miller’s research awards include the Curt Richter Award from the International Society of Psychoneuroendocrinology and the Norman Cousins Award from the Psychoneuroimmunology Research Society. Aside from his research endeavors, Dr. Miller is a Board Certified Psychiatrist and past examiner for the American Board of Psychiatry and Neurology.

Malú Tansey, PhD

Emory University School of Medicine

Dr. Malú Gámez Tansey obtained her B.S/M.S in Biological Sciences from Stanford University and her Ph.D in Physiology from The University of Texas Southwestern Graduate School in Dallas. She is a tenured Associate Professor of Physiology and a member of the Center for Neurodegenerative Disease (CND) at Emory University School of Medicine in Atlanta, Georgia. The main research interests of her laboratory include cellular and molecular mechanisms involved in regulation of glial activities and neuronal survival by Tumor Necrosis Factor (TNF) and identification of TNF-dependent signal transduction cascades and their molecular regulators underlying neuroinflammatory stress responses that promote neuronal apoptosis in cell-based and animal models of neuronal cell death with the long-term goal of developing novel therapeutics for the prevention and/or treatment of neurodegenerative diseases. Her research is supported with grants from The Michael J. Fox Foundation for Parkinson’s Research, the National Parkinson Foundation, the American Health Assistance Foundation, the HighQ/CHDI Foundation, and the National Institutes of Health (NIH).

Shi Du Yan, MD, MS

Columbia University

Shi Du Yan (Shirley ShiDu Yan), MD, is a Professor, Department of Pathology and Surgery, Taub Institute for Research on Alzheimer’s disease and the Aging Brain, Columbia University, New York. Dr. Yan’s research focuses on investigating cellular and molecular mechanisms of cell stress and survival in neurodegenerative disorders relevant to Alzheimer’s disease. She was the first to identify the specific cellular (RAGE) and mitochondrial targets of amyloid-beta peptide (Aβ) and found the evidence of Aβ-mediated mitochondrial, synaptic, and neuronal dysfunction. Dr. Yan was the first to describe RAGE, ABAD and cyclophilin D as the functional binding proteins for Aβ, and she and her research team are the major group investigating these paradigms. Her recent studies highlight the significant impact of mitochondrial Aβ on neuronal stress and cognitive decline relevant to the pathogenesis of Alzheimer disease. Dr. Yan and her research team‘s findings have been published in world-wide leading Journals including Nature, Science, Nature Medicine, Proceeding of National Academy Sciences, and first class of the professional Journals. Dr. Yan has authored 140 publications. Her research project is supported by National Institute of Health and Alzheimer Association. She received several awards including the Zenith Fellow Award from the Alzheimer’s Association in 2005. She is an active member of the scientific review committee for NIH, VA merit grant, Alzheimer’s association, and other foundation grants.

Raz Yirmiya, PhD

Hebrew University

Raz Yirmiya holds a Ph.D. in Neuroscience from UCLA. He is currently a Professor and director of the Inter-Departmental Program in Psychobiology at the Hebrew University of Jerusalem, Israel. He investigates the implications of immune-to-brain communication for psychiatric and neurological conditions. In his studies, he employed unique controlled and prospective experimental models of disease in humans, demonstrating that immune challenges, such as endotoxin administration, induce cytokine-mediated disturbances in behavioral, emotional and cognitive functions. In parallel studies using animal models he established the relationships between brain cytokines, prostaglandins and sickness behavior symptoms, and provided the first experimental evidence that illness-induced neurobehavioral disturbances resemble the characteristics of major depression and can be attenuated by chronic treatment with antidepressant drugs. Recently, Dr. Yirmiya discovered that brain interleukin-1 signaling plays a critical role in normal neurobehavioral processes, including hippocampal-dependent memory consolidation and neural plasticity, as well as various responses to acute and chronic stress. Dr. Yirmiya edited two books and published more than 145 papers in prestigious journals, including Nature Medicine, PNAS, Journal of Neuroscience, Molecular Psychiatry, Archives of General Psychiatry, Annals of Neurology, Biological Psychiatry, and Brain, Behavior and Immunity. He is currently the president of the PsychoNeuroImmunology Research Society (PNIRS) and an Associate Editor of Brain, Behavior and Immunity.

Sponsors

For sponsorship opportunities please contact Cristine Barreto at cbarreto@nyas.org or 212.298.8652.

Grant Support

This activity is supported by an educational donation provided by Amgen.

This event is funded in part by the Life Technologies™ Foundation.

Promotional Partners

Alzheimer’s Research Forum

The Dana Foundation

Abstracts

Inflammation and its Discontents: The Role of Inflammation in the Pathophysiology and Treatment of Depression

Andrew H. Miller, , MD, Emory University School of Medicine

Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain relevant to depression including monoamine metabolism, neuroendocrine function and neural plasticity. Of note, patients who are resistant to standard antidepressant treatments are especially likely to exhibit increased inflammatory markers. Administration of inflammatory cytokines is associated with the development of depressive-like behaviors in laboratory animals and humans, and treatment with antagonists of cytokines has been found to improve depressive symptoms in patients with inflammatory disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-know precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules including nuclear factor kappa B as well as interleukin 6. Studies in humans and laboratory animals chronically administered the inflammatory cytokine, interferon-alpha, have provided clues as to which brain regions are targeted by cytokines to influence behavior. Of special relevance in this regard are the basal ganglia and dopamine metabolism. Using functional magnetic resonance imaging and positron emission tomography along with in vivo microdialysis, data suggest that cytokines induce fundamental alterations in dopamine metabolism that are associated with reduced activation of reward circuitry in the basal ganglia. Such basal ganglia changes in turn correlate with cytokine-induced symptoms of anhedonia and fatigue. Translational implications of these findings include the application of immune-targeted or immune-relevant therapies to address behavioral pathologies in both medically ill and medically healthy depressed patients, especially those who are unresponsive to or intolerant of standard antidepressant strategies.

The Role of Inflammatory Cytokines in Behavioral and Neural Plasticity

Raz Yirmiya, PhD, Hebrew University

Studies conducted in my laboratory over the last two decades demonstrate that inflammatory cytokines in the brain, particularly microglial activation and production of pro-inflammatory cytokines such as interleukin (IL)-1, mediate the detrimental effects of chronic stress, infectious, autoimmune and neurodegenerative diseases on memory functioning and mood. In my talk, I will demonstrate the role of inflammatory processes in illness- and stress-induced memory disturbances and depression in humans and mice, and will discuss possible molecular, cellular and hormonal mechanisms underlying these effects. I will also argue that the involvement of inflammatory mediators in neurobehavioral pathology results from disruption of their normal 'physiological' roles in memory consolidation and neural plasticity.

Role of Proinflammatory Signaling in Neuronal Dysfunction in Alzheimer’s Disease: RAGE Molecules and their Potential Impact

Shi Du Yan, MD,MS, Columbia University

RAGE, a receptor for advanced glycation end-products, is an immunoglobulin-like cell surface receptor that is often described as a pattern recognition receptor due to the structural heterogeneity of its ligand. RAGE expresses in neurons, microglia, and vasculature including endothelial cells and smooth muscle cells. Increased expression of RAGE occurs under the pathological conditions such as neurodegenerative diseases including Alzheimer’s disease (AD) and multiple sclerosis, and diabetes. Multiple lines of evidence indicate that RAGE is an important cellular target for amyloid beta-peptide (Aß)-mediated neuronal and synaptic dysfunction relevant to the pathogenesis of Alzheimer’s disease (AD). Microglia are critical for amyloid beta peptide (Aβ)-mediated neuronal and synaptic failure. Aβ-induced inflammatory reactions, selective neuronal stress, and accumulation of Aβ are linked to microglial function. The effects of microglia are probably due to a range of cytotoxic and stimulatory mediators (cytokines, etc) released following cellular activation by A, as well as other factors in the AD milieu. RAGE expression was elevated in microglia of human AD brain as well as transgenic mice expressing Aβ. The studies in an in vitro microglial culture demonstrated that microglia with increased expression of RAGE produced higher levels of proinflammatory mediators (TNF-α and IL-1β) and oxidative stress in response to oligomer Aβ, which exaggerated neurotoxicity. Consistent with these results, transgenic mice overexpressing microglial RAGE and Aβ significantly enhanced neuroinflammatory response, as shown by increased cytokine productions and microglial infiltration and migration around the amyloid plaques. Neuropathological changes and impairment in learning/memory were observed at earlier age (3-4 months) of these mice. Notably, introduction of microglial DN-RAGE (dominant negative RAGE in which RAGE signal transduction was deficient) into transgenic APP mice attenuated the proinflammatory response, Aβ accumulation, neuronal and synaptic dysfunction, and cognitive deficits. Furthermore, phosphorylation of p38 and ERK1/2 was significantly diminished in DN-RAGE-expressed microglia induced by Aβ and in mice overexpressing DN-RAGE and Aβ. These results provide substantial evidence of the role of RAGE in Aβ-induced neuroinflammation leading to neuronal and cognitive dysfunction, suggesting that targeting RAGE as a key therapeutic strategy in AD, as RAGE antagonist has already been developed and have demonstrated a protective effect in animal model (Webster J et al.,Small-molecular inhibitors of the receptor for advanced glycation end-products (RAGE) are an effective therapy in animal models of Alzheimer's disease. Program and abstracts of the ICAD 2008: Alzheimer's Association International Conference on Alzheimer's disease. Chicago, IL, USA: 26-31, July 2008). The RAGE inhibitor has an excellent safety profile, and has been well-tolerated for over 10 weeks in patients with AD in oral treatments according to results of Phase II clinical study (Sabbagh MN et al., An oral anatagonist of the receptor for advanced glycation end-products (RAGE) is safe and well-tolerated in the treatment of Alzheimer's disease: Results from a Phase II study. Program and abstracts of the ICAD 2008: Alzheimer's Association International Conference on Alzheimer's disease. Chicago, IL, USA: 26-31, July 2008). RAGE inhibitors thus hold a potential for therapeutic significant advances in halting AD soon.

Role and Regulation of TNF-dependent Neuroinflammation in Models of Neurodegeneration

Malú Tansey, PhD, Emory University School of Medicine

Neuroinflammatory processes have been implicated in a number of neurodegenerative disorders including Parkinson’s disease (PD). A role for the pro-inflammatory cytokine Tumor Necrosis Factor (TNF) has been implicated in the non-autonomous cell death of nigral midbrain dopaminergic (DA) neurons. We investigated the role of soluble TNF-dependent neurotoxicity in acute and progressive nigral DA neuron death using novel engineered dominant negative TNF variants (DN-TNFs) or viral vectors encoding DN-TNFs in vitro and in vivo. DN-TNF gene transfer administered as late as two weeks after an acute neurotoxic insult attenuated microglia activation and halted further DA neuron loss in the chronic phase of the lesion. The implication of these studies is that timely targeted inhibition of soluble TNF bioactivity in the ventral midbrain may slow the progressive loss of nigral DA neurons and delay development of motor symptoms in PD.

Fibrinogen Signal Transduction as a Mediator and Therapeutic Target in Inflammation: Lessons from Multiple Sclerosis

Katerina Akassoglou, PhD, Gladstone Institute & UCSF

The blood protein fibrinogen as a ligand for integrin receptors functions as the molecular nexus of coagulation, inflammation and immunity. Fibrinogen extravasates in the nervous system after injury or disease associated with vascular damage or blood-brain barrier (BBB) disruption. In multiple sclerosis (MS), perivascular demyelination is accompanied by increased vascular permeability resulting to extensive deposition of fibrin. Our studies in animal models for MS have demonstrated that fibrinogen is not merely a marker of BBB disruption, but a mediator of neuroinflammation. Fibrinogen mediates pro-inflammatory functions in the nervous system by activating the Mac-1 integrin receptor (also known as CD11b/CD18 and complement receptor 3) in microglial cells. In vivo imaging in the mouse spinal cord using two-photon microscopy shows that microglia perform constant surveillance of blood vessel walls in myelinated areas. Pharmacologic or genetic disruption of the fibrinogen/Mac-1 interaction suppresses neurologic symptoms, inflammation and demyelination in Experimental Autoimmune Excephalomyelitis (EAE), a model of MS. Because blocking fibrinogen/Mac-1 interaction affects the proinflammatory but not the procoagulant properties of fibrinogen, strategies to target fibrinogen receptors within the tissue microenvironment could reveal selective and disease-specific agents for therapeutic intervention in neuroinflammatory diseases.

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