DC Element | Wert | Sprache |
dc.contributor.author | Tackenberg, Christian | |
dc.contributor.author | Grinschgl, S. | |
dc.contributor.author | Trutzel, A. | |
dc.contributor.author | Santuccione, A. C. | |
dc.contributor.author | Frey, M. C. | |
dc.contributor.author | Konietzko, U. | |
dc.contributor.author | Grimm, J. | |
dc.contributor.author | Brandt, Roland | |
dc.contributor.author | Nitsch, R. M. | |
dc.date.accessioned | 2024-01-04T14:09:02Z | - |
dc.date.available | 2024-01-04T14:09:02Z | - |
dc.date.issued | 2013 | |
dc.identifier.uri | http://osnascholar.ub.uni-osnabrueck.de/handle/unios/73422 | - |
dc.description.abstract | Aggregates of amyloid-beta (Aβ) and tau are hallmarks of Alzheimer's disease (AD) leading to neurodegeneration and synaptic loss. While increasing evidence suggests that inhibition of N-methyl-D-aspartate receptors (NMDARs) may mitigate certain aspects of AD neuropathology, the precise role of different NMDAR subtypes for Aβ- and tau-mediated toxicity remains to be elucidated. Using mouse organotypic hippocampal slice cultures from arcAβ transgenic mice combined with Sindbis virus-mediated expression of human wild-type tau protein (hTau), we show that Aβ caused dendritic spine loss independently of tau. However, the presence of hTau was required for Aβ-induced cell death accompanied by increased hTau phosphorylation. Inhibition of NR2B-containing NMDARs abolished Aβ-induced hTau phosphorylation and toxicity by preventing GSK-3β activation but did not affect dendritic spine loss. Inversely, NR2A-containing NMDAR inhibition as well as NR2A-subunit knockout diminished dendritic spine loss but not the Aβ effect on hTau. Activation of extrasynaptic NMDARs in primary neurons caused degeneration of hTau-expressing neurons, which could be prevented by NR2B-NMDAR inhibition but not by NR2A knockout. Furthermore, caspase-3 activity was increased in arcAβ transgenic cultures. Activity was reduced by NR2A knockout but not by NR2B inhibition. Accordingly, caspase-3 inhibition abolished spine loss but not hTau-dependent toxicity in arcAβ transgenic slice cultures. Our data show that Aβ induces dendritic spine loss via a pathway involving NR2A-containing NMDARs and active caspase-3 whereas activation of eSyn NR2B-containing NMDARs is required for hTau-dependent neurodegeneration, independent of caspase-3. | |
dc.language.iso | en | |
dc.relation.ispartof | Cell death & disease | |
dc.source | PubMed | |
dc.title | NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss | |
dc.type | journal article | |
dc.identifier.doi | 10.1038/cddis.2013.129 | |
dc.identifier.pmid | 23618906 | |
dc.identifier.url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641351 | |
dc.contributor.affiliation | Division of Psychiatry Research, University of Zurich, August-Forel-Strasse 1, 8008 Zurich, Switzerland. christian.tackenberg@bli.uzh.ch | |
dc.description.volume | 4 | |
dc.description.issue | 4 | |
dc.description.issue | e608 | |
dc.description.startpage | - | |
local.import.remains | U3 : Journal Article
Research Support, Non-U.S. Gov't
Journal Article
Research Support, Non-U.S. Gov't | |
local.import.sourcefile | ./Brandt_Roland_sk_Citavi_20231215.ris | |
crisitem.author.orcid | 0000-0003-0101-1257 | - |
crisitem.author.netid | BrRo587 | - |