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

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.

Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling

“…Extra-synaptic NMDA receptors activation was performed by addition of NMDA after synaptic NMDA receptors blockade as previously described [24]. The procedure was shown in Fig.…”

Human tau-dependent toxicity in APP transgenic cultures requires calcium influx through N-methyl-D-aspartate receptors

“…1A). In organotypic slices from APP transgenic mice Aβ induced a human tau-dependent cell death (Tackenberg 2013 [6] ). Here, we first confirmed this data by showing that EGFP-tau expression increased cytotoxicity assay luminescence in APP transgenic compared to non-transgenic cultures ( Fig.…”

“…NMDARs play an essential role for Aβ-induced neuronal dysfunction and inhibition of NMDARs protects against Aβ-induced synaptic loss (Tackenberg 2009 [4] ) (Shankar 2007 [5] ). Furthermore, the effect of Aβ on tau is mediated by NMDARs as blocking glutamate-binding to NMDARs prevents the induction of a taudependent neuronal cell death in APP transgenic cultures (Tackenberg 2013 [6] ). NMDARs can modulate intracellular signaling cascades via calcium influx into the cell.…”

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

“…According to the now well-established amyloid cascade hypothesis Aß acts upstream and mediates the neurodegenerative events, at least partially, through post-translational changes of tau via transmembrane signaling. This may involve both calcineurin signaling mediated by the glutamate receptor NMDAR and signaling of the energy state through SIRT1/AMPK [71,72]. Many components of these signaling cascades are conserved from yeast to humans.…”