Neuroinflammation

June 23 - July 1

Coordinator: Nicolas G. Bazan

LSU Center of Excellence in Neuroscience, New Orleans (USA)

Faculties:

Scott Brady, University of Illinois at Chicago, USA

Greg M. Cole, University of California Los Angeles, USA

Sally A. Frautschy, University of California Los Angeles, USA

Michael T. Heneka, Poliklinik für Neurologie, Bonn, Germany

V. Hugh Perry, University of Southampton, UK

Nicos A. Petasis, University of Southern California, USA

Boris Sakic, McMaster University, Hamilton, Canada

Joint Course with the Neuroscience Center of Excellence of the Louisiana State University Health Sciences Center

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.

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 began 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 medicinal chemistry and other 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 is an outline of topics that will be presented in the Course:

The contribution of neuroinflammation to neurodegeneration

A neglected area in the study of neurodegenerative diseases is how the associated immune response impacts on the diseased nervous system and how the inflammasome is involved in progression of conditions such as Alzheimer´s disease. Microglia represent the brain´s innate immune system, yet microglial driven immune responses may be detrimental or beneficial: attention will be dedicated to both hypotheses.

Sites of inflammation may also be at a considerable distance from neuronal perikarya: ALS and MS will serve as two examples on how local inflammation contributes to axonal pathology.

Neuroinflammation, neurodegenerative diseases, and aging The neuropathological and biochemical evidence for neuroinflammation having a bystander or a causal role in neurodegeneration will be presented including dilemmas on the epidemiology of NSAIDs for Alzheimer's or Parkinson's Diseases. Recent results of trials aimed at treatment and prevention will also be discussed.

On a therapeutic perspective, the best approach to limit chronic inflammation related to aging will be also debated. Whether modulatory rather than directly suppressive drugs should be used, whether a cycle of chronic inflammation can be broken with intermittent use of anti-inflammatory agents that limits toxic effects, and whether there is merit to the use of anti-TNFalpha or other passive immunization approaches to chronic inflammatory diseases are unanswered questions that await more dedicated experimental attention.

Microglia in homeostatic functions in the developing and adult nervous system

Recent efforts to define subclasses of pro-inflammatory and resolving macrophage and microglia differentiation states suggest that analogous to Th1 and Th2, innate immune cells have very distinct expression profiles and functional status in response to so-called "pro" or "anti" inflammatory cytokine exposure. How these profiles relate to specific stages of neuroinflammation and whether they may represent a therapeutic target capable of shifting the balance away from neurotoxic and toward beneficial functional activities will be a specific topic during the Course.

Neurotransmitter regulation of microglial functions: the involvement of the locus ceruleus in Alzheimer's disease

In Alzheimer´s disease, several brain stem nuclei degenerate and the locus coeruleus, appears to be involved early in disease progression. When, where and why does this nucleus degenerate? 
A specific role for microglial functioning in LC projection area has been suggested and the consequences for the overall pathological process will be analyzed.

Mechanisms: The role of ApoE genotype and glial activation in amyloid clearance

Modeling glial clearance of Aß aggregates (amyloid) in vitro and in vivo. ApoE4, the major risk factor for AD, alters neuroinflammation in many CNS disease states. The molecular mechanisms responsible for these effects and whether glial amyloid clearance is age and ApoE genotype-dependent will be discussed. It will be argued that ApoE pharmacogenomic and nutri-genomic effects related to both omega 3 and conventional NSAIDs need to be dealt with to make prevention possible.

Mechanisms: The significance in neuroinflammation of the selective enrichment, and avid retention, of omega-3 essential fatty acids in the nervous system.

The DHA metabolome gives rise to bioactive docosanoids (NPD1 -neuroprotectin D1- and other mediators) . These bioactive lipids are different than the eicosanoids, which are derived from the 20 C arachidonic acid family member of essential fatty acids not selectively enriched in the nervous system. However docosanoids and eicosanoids are active participants in neuroinflammation. NPD1 is promptly synthesized in response to oxidative stress, brain ischemia-reperfusion and neurotrophins. NPD1 modulates neuroinflammatory signaling and is neuroprotective in experimental stroke, oxidative-stressed retinal pigment epithelial cells; in human brain cells either expressing the double Swedish mutation or exposed to oligomer amyloid-β peptide, epileptogenesis and Parkinson's cellular models. The significance of NPD1 and of other lípid mediators in homeostatic modulation of neuroinflamation in age-related macular degeneration (and other retina degenerative diseases), cornea nerve regeneration, glaucoma, Alzheimer's, Parkinson's and stroke will be discussed.

Psychoneuroimmunology, fever, sickness behavior, and neuroinflammation

Neuroinflammation in Mental Disorders

Biomarkers of neuroinflammation

To detect and monitor active neuroinflammation is a challenge. How well imaging can probe inflammation and whether reliable CSF and plasma biomarkers exists will be matter for debate. Also, the possibility that these biomarkers might be used as a surrogate to monitor inflammation and might be altered by CNS diseases will be discussed

Pharmacologic approach to chronic neuroinflammatory diseases

Traditional and novel alternative therapeutic approaches will be examined in detail. Steroids and COX inhibitors have limitations for chronic use: what are novel therapeutic targets and what novel anti-inflammatory drugs are in the pipeline? Are there promising alternative NSAIDs? Is there potential for Omega-3 fatty acids?

Studies on the neuroinflammatory response to amyloid and how this changes with age will be addressed. In this respect, the relationship between tauopathy/ tangles and microglial activation and how the traditional Asian NSAID, the curry pigment curcumin, may suppress pathogenesis in animal models for amyloid, tauopathy and HD will be analyzed. Can curcumin be used clinically?

Nuclear hormone receptors may represent therapeutic targets in neurodegenerative disease. The function and modification of nuclear hormone receptors such as the peroxisome proliferator activated receptor gamma and the liver X receptor for in physiology and pathophysiology will be discussed with special emphasis on the fate of these receptors in neurodegeneration and their possible use as therapeutic targets in Alzheimer´s and Parkinson´s disease.

Finally, immunization may be used to arrest neurodegeneration. Experimental studies show that systemic immunization can be used to alert the immune system to the accumulation of amyloid in the brain: the immune system then plays a part in the removal of the amyloid. However, this approach to protein misfolding diseases is not without risks. The mechanisms, benefits and harms of immunotherapy for protein misfolding diseases will be discussed.

Dr Haydee Bazan (Lousiana State University, New Orleans) will serve as Guest Discussant throughout the Course.