Abstract
Amyloid beta (Aβ)-mediated synapse dysfunction and spine loss are considered to be early events in Alzheimer’s disease (AD) pathogenesis. N-methyl-D-aspartate receptors (NMDARs) have previously been suggested to play a role for Amyloid beta (Aβ) toxicity. Pharmacological block of NMDAR subunits in cultured neurons and mice suggested that NMDARs containing the GluN2B subunit are necessary for Aβ-mediated changes in synapse number and function in hippocampal neurons. Interestingly, NMDARs undergo a developmental switch from GluN2B- to GluN2A-containing receptors. This indicates different functional roles of NMDARs in young mice compared to older animals. In addition, the lack of pharmacological tools to efficiently dissect the role of NMDARs containing the different subunits complicates the interpretation of their specific role. In order to address this problem and to investigate the specific role for Aβ toxicity of the distinct NMDAR subunits in dentate gyrus granule cells of adult mice, we used conditional knockout mouse lines for the subunits GluN1, GluN2A and GluN2B. Aβ-mediated changes in synaptic function and neuronal anatomy were investigated in several-months old mice with virus-mediated overproduction of Aβ and in 1-year old 5xFAD mice. We found that all three NMDAR subunits contribute to the Aβ-mediated decrease in the number of functional synapses. However, NMDARs are not required for the spine number reduction in dentate gyrus granule cells after chronic Aβ-overproduction in 5xFAD mice. Furthermore, the amplitude of synaptic and extrasynaptic NMDAR-mediated currents was reduced in dentate gyrus granule of 5xFAD mice without changes in current kinetics, suggesting that a redistribution or change in subunit composition of NMDARs does not play a role in mediating Amyloid beta (Aβ) toxicity. Our study indicates that NMDARs are involved in AD pathogenesis by compromising synapse function but not by affecting neuron morphology.
Highlights
Amyloid beta (Aβ) deposition in the brain of Alzheimer Disease (AD) patients initiates a cascade of events that trigger synaptic dysfunction, spine loss and neuronal death
N-methyl-D-aspartate receptors (NMDARs) are involved in C-terminal 100 (CT100)-induced changes of synaptic function in young mice Synaptic dysfunction, one of the earliest events in AD pathology [51], is thought to be caused by overproduction of toxic Amyloid Beta (Aβ) species [30, 95]
We injected recombinant adeno-associated viruses (rAAVs) overexpressing CT100 into the dentate gyrus (DG) of young mice (P7) and observed a decrease in miniature excitatory post-synaptic current (mEPSC) frequency in CT100-overexpressing cells 9–10 weeks post injection (Table 1 and Additional file 1: S1f ), possibly suggesting that Aβ-toxicity reduces with brain development
Summary
Amyloid beta (Aβ) deposition in the brain of Alzheimer Disease (AD) patients initiates a cascade of events that trigger synaptic dysfunction, spine loss and neuronal death (reviewed in [26]). NMDARs are known to play an important role for synaptic plasticity in the healthy brain (reviewed in [88]). It has been speculated that altered NMDAR signalling is involved in the pathogenesis of several neurological diseases including AD (reviewed in [42]). One of the two types of FDA (U.S Food and Drug Administration) approved AD therapies targets NMDARs. the partial NMDAR antagonist Memantine alleviates cognitive impairments in Müller et al Acta Neuropathologica Communications (2018) 6:110 moderate-severe AD patients [68, 73, 83, 100].
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