December 7-10, 2003
This meeting focused on integrating neurological and immunological perspectives on glial inflammatory responses in chronic degenerative diseases, including HIV-1 associated dementia (HAD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD).
Session One: "What are the common factors and distinct differences in glial responses between neurodegenerative diseases?" was chaired by Patrick McGeer and Eugene Major. Bill Hickey (Dartmouth) presented a number of schemes by which the neurodegenerative diseases can be classified, such as by region of neuropathology or by the molecules affected. These groups represent new ways to consider related features of several diseases. Stuart Lipton (Burnham Institute) discussed various methods of cell death in response to injury, including apoptosis, necrosis, and autophagy. He suggested that excitotoxicity due to activation of microglia and subsequent cytokine release is one pathological feature that may be shared among different diseases. Richard Banati (Imperial College School of Medicine) presented data on a new ligand, PK11195, for neuroimaging studies of activated microglia. Stan Appel (Baylor College of Medicine) described glial activation in ALS prior to the onset of motor neuron damage.
Session Two: "Macrophage/microglial activation in neurodegenerative diseases" was chaired by Wolfgang Streit and Celia Brosnan. Gary Landreth (Case Western) spoke about how protein aggregates like Aβ may mediate an inflammatory response by binding a multi-receptor complex and activating intracellular signaling cascades that lead to microglial activation. Tika Benveniste (U Alabama) described signal transduction cross-talk in macrophage/microglial activation pathways, particularly the INF-γ and TNF-α signaling pathways. W. Sue Griffin (U Arkansas for Medical Sciences) suggested that the similar formation of amyloid plaques and neurofibrillary tangles in both Alzheimer's disease and older patients with Down syndrome present an opportunity to look at the timing of inflammation and plaque/tangle neuropathology in the brain. Howard Gendelman (Dana-Farber) discussed the "bipolar properties" of microglia, stressing effects in the nervous system that can be both good and bad.
Session Three: "Astrocyte Functioning/Dysregulation in Neurodegenerative Disease" was chaired by Bruce Ransom and Richard Ransohoff. Avi Nath (JHU) described astroglial activation initiated by HIV-1 viral proteins. Jeff Rothstein (JHU) discussed altered regulation of glutamate transport and glutamate toxicity in astroglial cells in ALS and MS. Iain Campbell (Scripps) shared data from transgenic mouse models designed to allow detection of local cytokine (IL-6, TGFβ, IFNα) production in response to injury, degeneration, autoimmune damage, or infection. Tony Wyss-Coray (Stanford) shared studies on the role of complement as a regulator of inflammation in the aging and damaged nervous system.
Session 4: The Upside of Inflammation: Can Neurotoxicity be Shifted to Repair? Chaired by Mark Mattson (NIA) and Linda Van Eldik (Northwestern U), session four focused on beneficial effects of inflammatory molecules. Carol Colton (Duke) discussed the good and bad effects of reactive oxygen and nitrogen species in the nervous system, particularly focusing on Alzheimer's disease. Robert Friedlander (Brigham and Women's Hospital) showed results of caspase inhibition in several animal models of neurological disease, including stroke, TBI, SCI, ALS, HD, and PD, and discussed potential clinical uses of minocycline, a drug that inhibits caspase activation. Michael Vitek (Duke University & COGNOSCI, Inc.) reviewed evidence that the presence of the APOE4 genotype, in addition to being predictive of Alzheimer's disease risk, also correlates with higher incidence of neurological symptoms of HIV infection (Corder EH, et al., HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998 Oct;4(10):1182-4.), faster progression in MS (Chapman J, et al., APOE genotype is a major predictor of long-term progression of disability in MS. Neurology. 2001 Feb 13;56(3):312-6.), and worse outcome after TBI (Crawford FC, et al., APOE genotype influences acquisition and recall following traumatic brain injury. Neurology. 2002 Apr 9;58(7):1115-8.) The common inflammatory features of these disorders suggest that APOE4 genotype could be associated with a greater (more toxic) immune response to CNS insult; Dr. Vitek showed data from studies using an APOE peptide to modify inflammatory CNS responses (Lynch JR, et al., APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem. 2003 Dec 5;278(49):48529-33. Epub 2003 Sep 24.) Voon Wee Yong (University of Calgary) described detrimental and beneficial aspects of matrix metalloproteinases in CNS disorders (Yong VW, et al., Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001 Jul;2(7):502-11.) The direction of these effects appears to depend on the type of injury, the cellular context and substrates available in the environment, and the timing after injury. Michal Schwartz (Weizmann Institute of Science) discussed the protective autoimmunity hypothesis, specifically that the same population of T cells can mediate autoimmunity and neuroprotection. She suggested that this may be a novel therapeutic approach for treating nervous system injury. Bruce Chesebro (Rocky Mountain Laboratories, NIAID) presented information on animal models of prion diseases that suggested astrocytes may release a toxic factor that contributes to neuronal damage in these diseases.
Session 5: "Animal models of neurodegenerative diseases" was chaired by Peter Davies (Albert Einstein School of Medicine) and Janice Clements (JHU). Eliezer Masliah (UCSD) presented a synopsis of animal models of Parkinson's disease and posed four questions that animal models can help to answer: 1) What is the structural basis of Lewy body-associated impairment; 2) Which form of alpha-synuclein is more toxic; 3) what is the sequence of molecular and cellular events in PD, and 4) where should we intervene? Jun Tan (University of South Florida) described animal models of Alzheimer's disease that reveal microglial influences on Aβ accumulation. Don Cleveland (UCSD) discussed experiments using the SOD-1 mouse model of ALS to determine whether genetics or cellular environment play a bigger role in SOD-1 toxicity. Christine Zink (Johns Hopkins) presented data on the pigtail macaque model of SIV neuropathogenesis. This model appears to be developing as a powerful tool for understanding lentiviral damage to the CNS. Richard Ransohoff (Cleveland Clinic) discussed the role of chemokines and signals activating microglia in neurotoxicity in vivo.
There was a "Poster Session for Young Investigators" where work studying inflammation in the CNS from various systems and viewpoints was presented. Presenters included Anuja Ghorpade (University of Nebraska), Monica Carson (Scripps), Brent Harris (Dartmouth), Gareth John (Albert Einstein), Viktor Longo (University of Southern California), Scott Wilson (University of Alabama), Colin Combs (University of North Dakota), Kalipada Pahan (University of Nebraska), Susan Wilt (Bronx VAMC), Kenneth Hensley (Oklahoma Medical Research Foundation), Jon Weinstein (University of Washington), Tsuneya Ikezu (University of Nebraska), and Natalie Streichenberger (Lyon).
Session 6: "Diagnostic and Therapeutic Approaches to Neurodegenerative Diseases" was chaired by Donald Price (Johns Hopkins) and Joseph Rogers (Sun Health Research Institute). Howard Gendelman (University of Nebraska) spoke of novel work using the peptide copaxone to stimulate the immune system as a vaccination approach to prevent damage to dopaminergic neurons in mice treated with MPTP, a model for Parkinson's disease. David Morgan (University of South Florida) presented an update of progress using vaccination approaches for prevention of Alzheimer's Disease in animal models. Marl Noble (University of Rochester) discussed Stem Cells as a potential therapy for neurodegenerative diseases in general, summarizing the trials using stem cells for Parkinson's Disease, and discussing the broader potential for use of stem cells to repair the damaged CNS.
Session 7: "Capstone Session"
Eugene Major (NINDS) and Patrick McGreer provided an overview of Session 1: In addition to symptomatic classification, many CNS diseases can now be classified by pathophysiological mechanism. Immune factors appear to play a role in diseases that are not traditionally associated with immunopathology, such as the neurodegenerative diseases. It will be important to emphasize early detection of these processes (perhaps by imaging) to aid in treatment and prevention.
Session 2 was reviewed by Wolfgang Streit and Celia Brosnan: There are a range of microglial activation states, or perhaps a range of microglial phenotypes, that influence CNS disease. Complex signaling processes are involved in microglial responses, and the environment of the brain is likely to impact these pathways (thus it will be important to do in vivo as well as in vitro work). A signaling pathway/wiring diagram would help to understand signaling effects on the microglial cell. This could be used as a tool in diagnosing the state of microglia within a tissue, and then used to manipulate microglial states. Microglial immunotherapy has potential for several neurological conditions.
Bruce Ransom and Richard Ransohoff reviewed Session 3: Astrocyte dysfunction directly affects neuron function or survival, because there is an inextricably cooperative relationship between these cell types for all brain activity. We don't know if microglial dysfunction has an effect on astrocyte and neuron function (or vice versa). (Ransom suggested some specific experiments, but I didn't catch them.) Priorities for the near future should be the identification of microglial-specific promoter sequences for use in transgenics. Better tools to identify astrocyte dysfunction, a registry of all mouse models available and a financial mechanism for sharing models were also identified as needs.
The review of Session 4 was moderated by Mark Mattson and Linda Van Eldik: There is growing knowledge about cellular effects of redox reactants, caspases, matrix metalloproteinases, T cells, and neuroinflammatory factors in different disorders, and in different ages and species. It is time to start thinking about developing drugs that target the inflammatory process, and time to set up the model systems that will be needed to screen compounds.
Session 5 was reviewed by Peter Davies and Janice Clements: Animal models will be essential to unravel the complex interactions during neuroinflammation. Early inflammatory responses can be beneficial/protective; a paradigm shift is occurring in the field regarding T cell involvement in inflammation and the fact that astroglial or microglial activation is not good or bad, but is context-dependent. There was discussion about whether artificial pressures put on the science (like reviewer preferences for single mechanism-driven models, etc.) are causing a widespread failure to translate basic science "cures" into clinical successes - "are we doing the real-life experiments?"
Session 6 was reviewed by Donald Price: The workshop was concluded with a call for initiatives to promote a more fully developed understanding of the variety and breadth of glial cell identity and function.
Last Modified March 23, 2011