Kurzfassung

Neurodegenerative diseases are brain diseases that are characterized by slowly progressing neuron dysfunction and cell death. Although heterogeneous in their causes, there are several similarities such as protein misfolding and accumulation of atypical proteins, mitochondrial dysfunction and induced cell death (apoptosis). Neurons undergo apoptotic cell death as a response to various detrimental factors. For example, over-activation of glutamate receptors of the NMDA receptor (NMDAR) type can...Neurodegenerative diseases are brain diseases that are characterized by slowly progressing neuron dysfunction and cell death. Although heterogeneous in their causes, there are several similarities such as protein misfolding and accumulation of atypical proteins, mitochondrial dysfunction and induced cell death (apoptosis). Neurons undergo apoptotic cell death as a response to various detrimental factors. For example, over-activation of glutamate receptors of the NMDA receptor (NMDAR) type can induce apoptosis. Interestingly, NMDARs are thought to be involved in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
            Considering the heterogeneity of neurodegenerative diseases, it is surprising that similar mechanisms were discussed for how NMDARs might be involved in the slowly progressing neuron dysfunction and cell death in the different diseases. A central hypothesis is an up-regulation and redistribution of NMDARs during the course of the disease resulting in increased extrasynaptic and decreased synaptic NMDAR numbers. This change in the expression could explain an augmented susceptibility of the neuron to glutamate-mediated neuron dysfunction and excitotoxic cell death as the activation of extrasynaptic NMDARs is thought to be detrimental, whereas that of synaptic NMDARs was shown to be protective. Moreover, two different NMDARs subunits, namely GluN2A and GluN2B, may play opposite roles in neurodegenerative diseases, since it is generally believed that in the adult brain synaptic NMDARs comprise to a large extend GluN2A-containing receptors, whereas most extrasynaptic NMDARs contain the GluN2B subunit.
            In this study we aim to investigate the hypothesis of the involvement of NMDARs in the pathogenesis of neurodegenerative diseases and of the differential role of GluN2A and GluN2B by using adult conditional NMDAR subunit knockout mice. To test if there are common mechanisms of how NMDARs play a role in different neurodegenerative diseases, we will focus on Alzheimer's disease and Huntington's disease. We will analyze if the deletion of NMDAR subunits (GluN1, GluN2A and GluN2B) ameliorates or deteriorates disease related changes in physiology and anatomy of cortical, hippocampal and striatal neurons in mice with virus-mediated expression of the disease-causing proteins amyloid β and mutant huntingtin and in established disease model mice. This study aims to shed light on the interaction of different molecules that are causal for the development of neurodegenerative diseases and might be of value for the improvement of their treatment especially when considering that several new drugs have been developed that block or modulate NMDAR subunits.» weiterlesen» einklappen