Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer's disease

Abstract

BackgroundAlzheimer’s disease (AD) pathology occurs in part as the result of excessive production of β-amyloid (Aβ). Metabotropic glutamate receptor 5 (mGluR5) is now considered a receptor for Aβ and consequently contributes to pathogenic Aβ signaling in AD.ResultsGenetic deletion of mGluR5 rescues the spatial learning deficits observed in APPswe/PS1ΔE9 AD mice. Moreover, both Aβ oligomer formation and Aβ plaque number are reduced in APPswe/PS1ΔE9 mice lacking mGluR5 expression. In addition to the observed increase in Aβ oligomers and plaques in APPswe/PS1ΔE9 mice, we found that both mTOR phosphorylation and fragile X mental retardation protein (FMRP) expression were increased in these mice. Genetic deletion of mGluR5 reduced Aβ oligomers, plaques, mTOR phosphorylation and FMRP expression in APPswe/PS1ΔE9 mice.ConclusionsThus, we propose that Aβ activation of mGluR5 appears to initiate a positive feedback loop resulting in increased Aβ formation and AD pathology in APPswe/PS1ΔE9 mice via mechanism that is regulated by FMRP.

Combining two repurposed drugs as a promising approach for Alzheimer's disease therapy

“…mGluR2, belonging to group II glutamate receptors, was found to be overexpressed in the hippocampus of AD patients56. Caraci et al demonstrated that a positive allosteric modulator of group II mGluR2 aggravated Aβ-induced neurotoxicity57, while knockout of group I mGluR5, considered as a co-receptor for Aβ58, attenuates cognitive impairment in a mouse model of AD59. APP has been shown to be rapidly translated in the synapses in response to DHPG, agonist of group I mGluRs60, and such activation stimulates the release of Aβ 1–42 in cortical synaptoneurosomes in a mouse model of AD, while stimulation of group II mGluRs triggers production and release of both Aβ 1–42 and Aβ 1–40 61.…”

Hippocampal metabotropic glutamate receptor long‐term depression in health and disease: focus on mitogen‐activated protein kinase pathways

“…However, it is vital to further examine mGluR-LTD in this disease as the signaling pathways associated with mGluR-LTD have been implicated in the generation of Ab, hyperphosphorylation of tau and loss of synapses, which are all involved in the pathology of AD. The potential importance of mGluR-LTD in Alzheimer's is supported by the observation that deletion or inhibition of mGluR5 rescued spatial learning and reduced Ab plaque load in an AD mouse model (Um et al 2013;Hamilton et al 2014).…”

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

“…Separately from PrP C coupling, other studies of AD models have implicated mGluR5 and altered glutamate signaling (Hamilton et al, 2014, 2016; Hu et al, 2014; Overk et al, 2014; Renner et al, 2010; Wang et al, 2004; Zhang et al, 2015). Glutamate activation of this metabotropic G protein-coupled receptor (GPCR) leads to multiple signal transduction pathways, including phospholipase C, inositol triphosphate, and intracellular calcium release, as well as Homer, Arc, eukaryotic elongation factor 2 (eEF2), and fragile X mental retardation protein (FRMP) regulation of protein translation at synapses, plus calcium/calmodulin-activated protein kinase II and Fyn kinase activation (Bhakar et al, 2012; Heidinger et al, 2002; Lüscher and Huber, 2010; Nicodemo et al, 2010; Um et al, 2013).…”

“…Both genetic loss and pharmacological inhibition studies have demonstrated that reduced mGluR5 activity alleviates synaptic and memory deficits in various AD-related models (Beraldo et al, 2016; Hamilton et al, 2014, 2016; Hu et al, 2014; Overk et al, 2014; Raka et al, 2015; Renner et al, 2010; Um et al, 2013; Wang et al, 2004; Zhang et al, 2015). However, none of these interventions have separated the mechanistic benefit as being due to inhibition of glutamate signaling versus Aβo/PrP C signaling versus a combination of both.…”