Neuroinflammation: Molecular Principles and Translational Approach
August 23 - 30, 2014
Coordinator: Nicolas G. Bazan
LSU Center for Excellence in Neuroscience, New Orleans, USA
Scott Brady, University of Illinois, Chicago (USA)
David Brody, Washington University School of Medicine, St Louis (USA)
Marianne Schultzberg, Karolinska Institute, Stockholm (Sweden)
Thomas Moeller, Lundbeck Research, Paramus, USA
Michael T. Heneka, University of Bonn (Germany)
Haydee Bazan, LSU Center for Excellence in Neuroscience, New Orleans (USA)
The central nervous system is often referred to as an immunologically privileged site. While the blood–brain barrier (BBB) protects the central nervous system (CNS) from peripheral immune and inflammatory activation, the CNS is also able to induce the protective innate immune system in response to injury, including trauma, infection, stroke and neurotoxins. This acute inflammatory response is short-lived and generally beneficial in neutralizing potential threats to the CNS by minimizing cellular damage. On the other hand, a sustained chronic neuroinflammatory response can be detrimental and initiate neuronal damage, neuronal circuits impairments, astrocytic and microglia involvement and neurodegeneration via long-lasting formation and accumulation of neurotoxic proinflammatory mediators. New knowledge has revealed that macrophage lineage resident cells, microglia, perivascular macrophages and the other macrophage populations are engaged in homeostatic functions in the developing and adult nervous system. A critical reappraisal of their function is currently in progress in order to ascribe to these cells their full significance in pathophysiology of several neurological disorders and to understand how comorbid systemic disease and associated immune response impacts the nervous system and its inflammatory response.
The CNS's innate immune response involves intricate signaling circuitry and cellular networks. What was once considered an immune-privileged site is now recognized as having the ability to synthesize and release reactive molecules and pro-inflammatory mediators, as well as a capacity to respond to injury with anti-inflammatory, pro- homeostatic mechanisms. Understanding CNS immunity requires attention to the temporal relationship between the inflammatory response and injury. Acute inflammation is the immediate response that occurs at the initiation of injury. When the BBB is compromised, peripheral blood components such as polymorphonuclear leukocytes have access to the CNS. These cells play part of the defense response and when excessively deployed in the interstitial space they contribute to cell damage. When acute inflammation does not contribute to repair and then cease within a relatively short time period, inflammation becomes chronic and often pathological. Recent advances have begun to define protective, reparative inflammatory responses that set in motion resolution of neuroinflammation thus limiting or abrogating sustained damage. Several potent mediators that modulate the neuroinflammatory response, induce overall homeostasis and attenuate apoptotic neuronal damage are identified.
The Course is aimed at reaching a comprehensive understanding of the cellular and molecular mechanisms, experimental models, and methodological approaches to study neuroinflammation. These will include innovative strategies for emerging targets for clinical translation and pharmaceutical intervention. Moreover, the Course will be a forum where basic and clinical researchers from diverse disciplines can meet, interact, and bring cross-disciplinary insights on new basic findings to the translational stage.
The following are specific topic, which, among others, will be focus of discussion and analysis.
Neurotransmitter Regulation of Microglial Functions: The Locus Ceruleus involvement in Alzheimer Disease
In Alzheimer´s disease, several brain stem nuclei degenerate. Very early during the course of the disease, probably during the mild cognitive impairment (MCI) stage, the locus ceruleus, chief source of norepinephrine in the brain, is already compromized. When, where and why does this nucleus degenerate? The specific role for microglial functioning in locus ceruleus projection area and the consequences for disease progression will be a topic for discussion. Also, the function and modification of nuclear hormone receptors such as the peroxisome proliferator activated receptor gamma and the liver X receptor in physiology and pathophysiology will be addressed. A special emphasis will be put on the fate of these receptors in neurodegeneration and their possible use as therapeutic targets in Alzheimer´s and Parkinson´s disease.
Inflammation and Axonal Degeneration: ALS and MS
Inflammatory pathways are typically activated in neurodegenerative diseases, but sites of inflammation may be a considerable distance from neuronal perikarya. How does local inflammation contribute to axonal and synaptic pathology? Amyotrophic Lateral Sclerosis and Multiple Sclerosis will serve as two examples of distinct pathologies with well-established inflammatory components.
Cell Death Pathways and Neurodegeneration
Neuronal cell death is a late event in most neuropathologies and blocking cell death may not prevent progression of neurological symptoms. Reframing the consideration of cell death in the nervous system to include early stages of axonal degeneration allows a focus on an understanding of the roles played by apoptotic signaling pathways in neurodegenerative diseases and synaptic connectivity.
Control of Chronic Neuroinflammatory diseases: Traditional and Novel Alternative Approaches
Steroids and COX inhibitors have important successes but limitations for chronic use. What are the targets and what novel anti-inflammatory drugs are in the pipeline? Are there promising alternative NSAIDs? Our focus will be on the potential for Omega-3 fatty acids.
Biomarkers of Neuroinflammation
How well can imaging probes detect and monitor active neuroinflammation? What are best CSF biomarkers? Are there any consistent plasma biomarkers? How are these markers altered by CNS diseases? Can any biomarker be used as a surrogate to monitor inflammation?
Neuroinflammation and Neurodegenerative Diseases of Aging
What is the neuropathological and biochemical evidence for a bystander or causal role? We will consider the evidence that the role of innate immune activation is stage-dependent. What is inconsistent and consistent in the epidemiology of NSAIDs for Alzheimer's or Parkinson's Diseases? What are the results of trials aimed at treatment and prevention? What is the best approach to limit chronic inflammation related to aging? Should we use modulatory rather than directly suppressive drugs? Can we break a cycle of chronic inflammation with intermittent use of anti-inflammatory agents that limits toxic effects? Is there any merit to the use of anti-TNFalpha or other passive immunization approaches to chronic inflammatory diseases?
Fever, Sickness Behavior, and Neuroinflammation
Immune "privilege" and immune capacity of the brain will be discussed together with cerebrospinal fluid physiology, transport mechanisms, epiplexus (Kolmer) cells, expression of cell adhesion molecules, microglia, and cytokine receptors on neurons and endocrine glands. Finally, the emerging field of behavioral dysfunction in systemic autoimmunity and inflammation will be addressed analysing the effects of these conditions on the limbic system, cognitive function and brain morphology.
The significance of docosanoid lipid mediators derived from omega-3 essential fatty acids in neuroinflammation
The identification of an endogenous lipid mediators made on demand at the onset of homeostasis disturbances, uncompensated oxidative stress and unresolved neuroinflammation will be discussed. The molecular principles that govern the production and bioactivity of Neuroprotectin D1 (NPD1) in experimental stroke, epilepsy, age-related macular degeneration, Alzheimer's, Parkinson's and other diseases will be highlighted. The following specific aspects will be presented: targeted transcription factors; COX-2; neurotrophins as agonists for NPD1 synthesis; new molecular imaging to open the DHA lipidome; aspirin-triggered NPD1 biosynthesis in the stroke penumbra; NPD1 in the homeostatic regulation of photoreceptor cell integrity; neuroinflammation and resolution in neurodegenerative diseases.
In addition, focus will be placed on:
Microglial response to CNS Trauma: Acute and chronic cellular inflammation
Immunosuppressive effects of CNS injury: Modulation of innate and adaptive immunity
Preclinical and clinical therapeutic trials targeting inflammation following traumatic brain injury: The two-edged sword
Industry's approach to drug discovery in neuroinflammation: reproducibility and wrong statistics.
Microglia as a potential target in Huntington's disease and other pathologies.