S14IDENTIFICATION OF NEUROINFLAMMATION IN THE BRAIN IN VIVO AND IN VITRO AND THERAPEUTIC STRATEGIES TO COMBAT ITS PROGRESSIONS14.1INFLAMMATORYn PROCESSES IN NEURODEGENERATIVE DISEASESS14.2IMAGING NEUROINFLAMMATION IN ALCOHOLISMS14.3CAN PERIPHERAL MARKERS INDICATE NEUROINFLAMMATION?S14.4INFLAMMASOMEn INDUCTION REGULATES HIPPOCAMPAL NEUROGENESIS AND DEPRESSION

摘要

Changes in morphology in specific brain regions are observed in various neurodegenerative diseases, e.g. Parkinson's and Alzheimer's diseases as well as in chronic alcohol abusers and adolescents involved in ‘binge dirnking’. Such changes are known to be associated with alterations in motor function as well as in cognitive impairment. The exact triggers for each of these neurodegenerative processes are unknown, although alcohol and its metabolite acetaldehyde contribute to alcohol-induced brain damage. A common factor in all of these diseases is the occurrence of neuroinflammation, which occurs at an early stage of the disease process and drives the disease pathology. The signalling pathways that are involved in such neuroinflammation include various transition metals, iron and copper, mitochondrial dysfunction as well as activation of the innate immune system. Metals as well as alcohol metabolism can generate reactive oxygen species that can initiate lipid peroxidation by attacking polyunsaturated fatty acids in membrane phospholipids, generating a family of reactive aldehydes, which can undergo Michael-type additions to protein thiol, imidazole and amino groups. Together with other oxidative modifications, this generates protein carbonyls, causing protein denaturation and aggregation. In turn, this overwhelms the ubiquitin/proteasome system, which can no longer eliminate these defective, damaged proteins. Aggregates of these ubiquinated proteins are a prominent pathological feature found within intracellular inclusion bodies in specific brain regions in many ‘protein conformational’ neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS and Huntington's disease.