Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss

Abstract

Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-d-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β-amyloid peptide (Aβ) in AD models. NMDARs can trigger intracellular cascades via Ca2+ entry, however, also Ca2+-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aβ. We show that endogenous Aβ as well as exogenously added synthetic Aβ oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca2+ chelator BAPTA or open-channel blockers MK-801 or memantine. Aβ increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aβ-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca2+ flux for synaptic degeneration by Aβ. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aβ oligomers. Our data suggest that Aβ induces the activation of p38 MAPK and subsequent synaptic loss through Ca2+ flux- and G protein-independent mechanisms.

Separate Ionotropic and Metabotropic Glutamate Receptor Functions in Depotentiation vs. LTP: A Distinct Role for Group1 mGluR Subtypes and NMDARs

“…Another plasticity-relevant pathway that has been implicated in metabotropic NMDAR actions is the activation of p38 MAPK (Nabavi et al, 2013; Birnbaum et al, 2015) which has been shown to be central to DP (Liang et al, 2008) and AMPAR endocytosis (Huang et al, 2004) However, the two pathways mentioned above are just two options how mGluR1 and metabotropic NMDAR actions could control the expression of DP. Future studies are required to identify the precise signaling mechanisms.…”

Dehydroevodiamine·HCl enhances cognitive function in memory-impaired rat models

“…A change in intracellular calcium levels is involved in the pathogenesis of AD [4546]. In particular, increased intracellular calcium is related to cognitive impairment through neuronal degeneration such as Aβ accumulation and synaptic loss [47]. Aβ decreases dendritic spine density, suppresses long-term potentiation (LTP), facilitates long-term depression (LTD), and impairs learning and memory [48].…”

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

“…To determine whether tau toxicity in APP transgenic cultures was mediated by ion flux through NMDA receptors, we first treated cultures with clinically relevant concentrations (1 µM and 10 µM, according to (Xia 2010 [10] )) of the NMDAR open channel blocker memantine. 1µM Memantine has been shown to block synaptic transmission in organotypic slices (Birnbaum 2015 [9] ). At both concentrations, memantine treatment completely abolished tau-dependent cell death in APP transgenic cultures (Fig.…”

“…independent of ion flux, has also been described (Nabavi 2013 [7] ) (Tamburri 2013 [8] ). It has been recently shown that oligomeric Aβ caused synaptic loss in hippocampal slice cultures via NMDAR signaling but independently of calcium influx (Birnbaum 2015 [9] ). In the present study we investigated, whether the tau-dependent neuronal cell death in APP transgenic cultures depends on ionotropic (calcium influx) or metabotropic NMDAR functions.…”