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| Home > Publications Database > NMDA Receptor-Dependent Amyloid Beta Toxicity in the Context of Alzheimer’s Disease |
| Dissertation / PhD Thesis | DZNE-2020-00249 |
2016
Abstract: The amyloid beta (Aβ) protein is known to mediate large parts of the pathology seen in Alzheimer’s disease (AD). Previous studies suggested that N-methyl-D-aspartate receptors (NMDARs) mediate some of the Aβ toxicity. However, it is not known in detail which NMDAR subunit plays a role. In this study, I investigated the involvement of the NMDAR subunits GluN1, GluN2A and GluN2B in Aβ toxicity by genetically deleting single subunits in individual neurons via injection of Cre-recombinase expressing AAVs into the brain of adult mice in which the respective NMDAR genes were flanked by loxP-sites (GluN1fl/fl, GluN2Afl/fl, and GluN2Bfl/fl). Aβ toxicity was induced either short-term by injection of AAVs overexpressing CT100(I716F) which leads to increased Aβ42 production, or long-term by transgenic overproduction in the 5xFAD mouse model. Both approaches allowed me to demonstrate that NMDAR subunits are indeed involved in Aβ toxicity in adult mice. Aβ induces a decrease in functional synapse number which is prevented by deletion of the GluN1 and GluN2B subunit and partially prevented by deletion of the GluN2A subunit. Furthermore, short-term Aβ overproduction induced an increase in spine number which was prevented by GluN1 and Glu2A deletion. Spine loss in the 5xFAD mouse line could be partially rescued by GluN1 and GluN2B deletion. In summary, the results of my thesis demonstrate the importance of both the GluN2A and Glun2B subunit in Aβ toxicity and suggest that AD treatment with NMDAR blockers might be beneficial when treatment is started early.
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