NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss

Aggregates of amyloid-beta (A β ) 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 A β - and tau-mediated toxicity remains to be elucidated. Using mouse organotypic hippocampal slice cultures from arcA β transgenic mice combined with Sindbis virus-mediated expression of human wild-type tau protein (hTau), we show that A β caused dendritic spine loss independently of tau. However, the presence of hTau was required for A β -induced cell death accompanied by increased hTau phosphorylation. Inhibition of NR2B-containing NMDARs abolished A β -induced hTau phosphorylation and toxicity by preventing GSK-3 β 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 A β 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 arcA β 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 arcA β transgenic slice cultures. Our data show that A β 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.