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"Molecular
Mechanisms of Neurodegeneration and Neuroprotection -
Experimental Approaches and the Diseased Brain" September 9-11, 2004, Leipzig, Germany
The Study Group Neurochemistry which is a part of the German Society for Biochemistry and Molecular Biology, regularly organizes a meeting each year in Germany. One of the aims of the annual meetings is to provide a forum for PhD students and young post-doctoral scientists to meet well-known experts in selected research fields as well as to present and discuss their recent research findings. This should be achieved by providing a high standard of the scientific programme while keeping the registration fees for PhD students as low as possible. From the pool of submitted poster abstracts, highly interesting findings are selected for short communications that will usually be presented by PhD students and young post-docs. This year´s conference was organised by the Paul Flechsig Institute for Brain Research in Leipzig and particularly focused on recent developments in understanding the molecular mechanisms of neurodegeneration and neuroprotection including novel experimental approaches and its relevance in treating neurodegenerative disorders. The meeting was generously supported by the International Society for Neurochemistry (ISN) and the Interdisciplinary Centre for Clinical Research (IZKF) of the University of Leipzig as well as Deutsche Forschungsgemeinschaft (DFG). It was the intention to provide a forum to discuss novel developments in understanding those mechanisms leading to neurodegeneration including Alzheimer, Parkinson, prion diseases, as well as vascular associated alterations and to highlight potential clinical implications. During four symposia the most recent developments in this field were presented by 14 plenary lectures and 13 short communications to about 120 participants from 13 countries worldwide such as China, Germany, Hungary, Israel, Italy, Jugoslavia, Sweden, Spain, Slovenia, Switzerland, Russia, UK, USA, including a high number of PhD students and junior scientists. Moreover, during the poster session a total of 66 poster contributions were discussed in a stimulating and lively atmosphere. The meeting abstracts as well as most of the plenary lectures were published as review-like articles in a Special Issue of the International Journal of Developmental Neuroscience (vol. 22, no. 7, 2004). Understanding the aetiology of major neurodegenerative diseases and identifying ways of early detection has become an increasingly important approach in treatment and prevention of such diseases. It is generally believed that all of the neurodegeneration-inducing insults ultimately lead to the initiation of a common signalling cascade of neuronal cell death, which manifests clinically as loss in distinct neurological functions. Such degenerative events are usually accompanied by counteracting, compensatory regenerative mechanisms. Therefore, elucidation of the common mechanisms underlying neurodegeneration and regeneration would allow establishment of strategies to intervene in the progression of neurodegeneration and to support regenerative processes. In this respect, the meeting has particularly addressed the roles of nicotinic acetylcholine receptors (A. Nordberg, Sweden), acetylcholinesterase (H. Soreq, Israel), neuroinflammation (Reiser, Germany), stress-related signaling cascades (Herdegen, Germany), and pathogenic proteins (b-amyloid, tau, prion) in neurodegeneration and neuroprotection (T. Arendt, Germany; E. Mandelkow, Germany; Ch. Richter-Landsberg, Germany; S. Roßner, Germany), as well as pathophysiological consequences of neuronal injuries (R.J. Perez-Polo, USA). Model systems that closely simulate cellular degeneration observed in brains with neurodegenerative disease (J. Götz, Switzerland; T. Herdegen, Germany; Harkany, Sweden) as well as specific proteomic and functional genomic approaches to understanding function (C.M. Morris, U.K.) have been reviewed. The symposium on molecular mechanisms of pathological filament/amyloid formation in nerve cells and glia started with the contribution by E. Mandelkow (Hamburg, Germany) who beautifully reviewed our recent knowledge on principles of aggregation of tau protein into Alzheimer paired helical filaments. The role of stress proteins and proteasome inhibition on tau-inclusion body formation in oligodendroglia was highlighted by Ch. Richter-Landsberg (Oldenburg, Germany) demonstrating that posttranslational modification of tau, heat shock protein induction and alterations of the proteasomal system are involved in the neuropathological events leading to aggregate formation and degeneration. The presentaion by J. Götz (Zürich, Switzerland) discussed the usefulness of tau transgenic mouse and tissue-culture models to test the amyloid cascade hypothesis, and provided alternative hypotheses to explain also the sporadic forms of Alzheimer´s disease culminating in the suggestion of redefining Alzheimer´s disease based on biochemical events rather than phenotype. A functional role of Munc13-1, a presynaptic protein linked to synaptic vesicle priming, in the metabolism of the amyloid precursor protein was suggested by S. Roßner (Leipzig, Germany) which was based on investigations of Munc13-1 knock-out mice and human neuroblastoma cells transfected with wild-type and mutant Munc13-1 constructs. In the symposium related to plastic-adaptive changes and neurodegenetation, the contribution by T. Arendt (Leipzig, Germany) provided strong evidence of a link between neuronal plasticity and paired helical filament (PHF)-like phosphorylation of tau, which further supported the suggestion that failures in synaptic plasticity may represent early events in the course of Alzheimer´s disease. In this regard, hibernation was exploited as a model to study the regulation of PHF-like tau-phosphorylation and its cell biological sequelae under physiological conditions. CNS trauma produces death of neurons and oligodendrocytes at and around the injury site. J.R. Perez-Polo (Galveston, USA) discussed the extra- and intracellular signals that trigger apoptotic cascades after trauma and demonstrated a major involvement of Bcl-xL and Bax. H. Soreq (Jerusalem, Israel) presented an overview on our recent knowledge of the role of acetylcholinesterase in neurodegenerative diseases, and provided further evidence that acetylcholine acts as a stress-response-regulating transmitter and that altered acetylcholine levels are associated with changes in the alternative splicing of pre-mRNA transcripts in neurons and in peripheral blood cells. Stress-responses are accompanied by an alternative splicing pattern of AChE pre-mRNA to induce overproduction of the neuronal AChE-R variant. In another symposium dealing with experimental approaches and its relevance to the diseased brain, T. Harkany (Stockholm, Sweden) presented a novel approach to selectively isolate GABAergic inhibitory neuron subsets to investigate their specific morphological and electrophysiological diversity. Studies of perisomatic inhibitory cells containing either parvalbumin or cholecystokinin revealed major differences in the temporal dynamics of their functional differentiation, and their dependence on target-derived signals like brain-derived neurotrophic factor and endocannabinoids. Prion infections of the central nervous system are characterised by a reactive gliosis and the subsequent degeneration of neuronal tissue. The contribution by M. Baier (Berlin, Germany) discussed the mechanisms of prion-induced glia activation and subsequent cytokine/chemokine secretion and its role in prion infection and disease progression using transgenic animal approaches. C.M. Morris (Newcastle upon Tyne, U.K.) provided an overview on tools such as microarray based gene expression profiling and 2-D and multidimensional proteomic methods which are uncovering functional components to a wide variety of neuroscience paradigms, and suggested that the application of these technologies is set to become standard in analysis in next future. The meeting concluded with a symposium on neuroprotection, in which A. Nordberg (Stockholm, Sweden) reported on the effect of nicotine in reducing insoluble beta-amyloid in the cortex of transgenic APPsw mice, while brain alpha, beta or gamma secretase-like activities, as well as NGF or BDNF protein expression remained unaffected. This effect seems to be mediated through the alpha7 nicotinic acetylcholine receptor, but the mechanisms underlying the nicotine´s amyloid-reducing effect still require further elucidation. The contribution by G. Reiser (Magdeburg, Germany) demonstrated in an in vitro model of stroke/ischemia (oxygen/glucose deprivation) that inhibition of Ca2+-independent phospholipase A2 and addition of the fatty acid docosahexaenoic acid (DHA) had neuroprotective activity, suggesting that both the enzyme and DHA synthesis are promising targets for treatment of inflammatory related disorders in the brain. T. Herdegen (Kiel, Germany) discussed the pathophysiological functions of JNK isoforms by investigating the effect of neuronal injuries in a number of knock-out mice with selective deletions of JNK1, JNK2 or JNK3 and provided evidence of opposite effects of JNK1 and JNK3 in medaiting neuronal cell loss or survival. Finally, J.W. Bartsch (Bielefeld, Germany) presented data suggesting that extracellular proteolysis by metalloproteases such as ADAM8 may play a role in neuroprotection. Studies in the ALS-like mouse model Wobbler demonstrated enhanced ADAM8 expression in CNS regions exhibiting neurodegeneration. Wobbler mice that are lacking ADAM8 expression demonstrated even a more strikingly enhanced neurodegenerative pathology. Amount allocated to speakers of plenary lectures of the symposia to reimburse their travel and accommodation expenses: Agneta Nordberg €
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