000144807 001__ 144807
000144807 005__ 20230726100441.0
000144807 037__ $$aDZNE-2020-00249
000144807 041__ $$aEnglish
000144807 1001_ $$0P:(DE-2719)2810465$$aMüller, Michaela$$b0$$eFirst author$$udzne
000144807 245__ $$aNMDA Receptor-Dependent Amyloid Beta Toxicity in the Context of Alzheimer’s Disease$$f - 2016-03-07
000144807 260__ $$c2016
000144807 300__ $$a101 pages, Ill.
000144807 3367_ $$2DataCite$$aOutput Types/Dissertation
000144807 3367_ $$2ORCID$$aDISSERTATION
000144807 3367_ $$2BibTeX$$aPHDTHESIS
000144807 3367_ $$02$$2EndNote$$aThesis
000144807 3367_ $$0PUB:(DE-HGF)11$$2PUB:(DE-HGF)$$aDissertation / PhD Thesis$$bphd$$mphd$$s1689153471_3266
000144807 3367_ $$2DRIVER$$adoctoralThesis
000144807 502__ $$aDissertation, Ruprechts-Karls-Universität Heidelberg, 2016$$bDissertation$$cRuprechts-Karls-Universität Heidelberg$$d2016
000144807 520__ $$aThe amyloid beta (Aβ) protein is known to mediate large parts of the pathology seen in Alzheimer’s disease (AD). Previous studies suggested that N-methyl-D-aspartate receptors (NMDARs) mediate some of the Aβ toxicity. However, it is not known in detail which NMDAR subunit plays a role. In this study, I investigated the involvement of the NMDAR subunits GluN1, GluN2A and GluN2B in Aβ toxicity by genetically deleting single subunits in individual neurons via injection of Cre-recombinase expressing AAVs into the brain of adult mice in which the respective NMDAR genes were flanked by loxP-sites (GluN1fl/fl, GluN2Afl/fl, and GluN2Bfl/fl). Aβ toxicity was induced either short-term by injection of AAVs overexpressing CT100(I716F) which leads to increased Aβ42 production, or long-term by transgenic overproduction in the 5xFAD mouse model. Both approaches allowed me to demonstrate that NMDAR subunits are indeed involved in Aβ toxicity in adult mice. Aβ induces a decrease in functional synapse number which is prevented by deletion of the GluN1 and GluN2B subunit and partially prevented by deletion of the GluN2A subunit. Furthermore, short-term Aβ overproduction induced an increase in spine number which was prevented by GluN1 and Glu2A deletion. Spine loss in the 5xFAD mouse line could be partially rescued by GluN1 and GluN2B deletion. In summary, the results of my thesis demonstrate the importance of both the GluN2A and Glun2B subunit in Aβ toxicity and suggest that AD treatment with NMDAR blockers might be beneficial when treatment is started early.
000144807 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x0
000144807 8564_ $$uhttps://d-nb.info/1093427043
000144807 909CO $$ooai:pub.dzne.de:144807$$pVDB
000144807 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810465$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
000144807 9131_ $$0G:(DE-HGF)POF3-341$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vMolecular Signaling$$x0
000144807 9141_ $$y2016
000144807 920__ $$lyes
000144807 9201_ $$0I:(DE-2719)1013023$$kAG Engelhardt$$lSynaptic Signalling and Neurodegeneration$$x0
000144807 980__ $$aphd
000144807 980__ $$aVDB
000144807 980__ $$aI:(DE-2719)1013023
000144807 980__ $$aUNRESTRICTED