Neuroscience and Immunology

Agenda

*Presentation times are subject to change.

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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