Aktivierung phagozytierender Zellen durch "Advanced Glycation Endproducts" und beta-Amyloid-Implikationen für die Pathogenese der Alzheimer'schen Demenz
Year: 2001
Type: dissertation
Abstract: Senile plaques are a hallmark in Alzheimer's Disease progression.These plaques consist mainly of fibrillar β-amyloid (Aβ), which can be modified by glycation.In addition these plaques contain so called AGEs "Advanced Glycation Endproducts", emerging from nonenzymatic glycated proteins.Subsequent dehydration, condensation and oxidation produces a heterogenous group of heterocyclic, coloured and fluorescent compounds.These AGE modified proteins are resistant to proteases and their formation is irreversible.AGEs and Aβ are able to activate Microglia cells, resulting in a neurotoxic effect, with several hypothesis of how microglia contribute to neuronal cell death.To investigate the neurotoxic effect murine microglia cells were used.The NF-κB translocation into the nucleus was taken as an indicator of microglial activation.In this work conditions were investigated, that are necessary to activate murine microglia cells by AGE stimulation.High molecular weight hyaluronic acid from extracellular matrix, in its native form, is inhibiting activation of microglia cells in vitro.In contrast NF-κB was activated in AGE stimulated microglia cells in the presence of low molecular weight hyaluronic acid fragments.Here it was shown that the ability to activate microglia cells is inversly proportional to the average size of the hyaluronic acid.The ability for activation of microglia cells was reduced only in parts by other extracellular matrix glycosaminoglycans, like D-glucuronic acid, N-acetylglucosaminoglycane or chondroitine-4-sulfate.Aβ and AGEs release reactive oxyen species during their develompent, which were shown to be able to cleave hyaluronic acid into small fragments.The signal transduction of AGE activated microglia cells was examined by measurement of NF-κB activation reduced by different inhibitors.A complex network of signaling pathways was detected, without revealing a certain receptor.Therefore an "in vitro model" was established, to find out the main neurotoxic component in the reaction of microglia cells.Again the signaling pathways were inhibited pharmacologically, using the cell free medium produced by these microglia cells as "conditioned medium" in neuronal cell culture.The murine neuronal cells were tested for their surviving in the conditioned medium, to correlate activated signal pathways with neurotoxicity.Inhibition of translation or transcription in microglia cells led to no reduction of the neurotoxic effect of the conditioned medium, nor did the inhibition of the mitochochondrial respiratory chain or the radical sources xanthine oxidase, lipoxygenase
Author: Arne Neumann
Language: German
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3171458202