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Hamilton A, Vasefi M, Vander Tuin C, McQuaid RJ, Anisman H, Ferguson SS. Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model. Cell Rep. 2016 May 31;15(9):1859-65. Epub 2016 May 19 PubMed.
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UT Southwestern Medical Center at Dallas
This is an interesting paper by Hamilton and colleagues that supports the idea that overactivation of mGluR5 by amyloid oligomers, and resulting dysregulated calcium signaling at synaptic locations, play an important role in AD. Previous studies already implicated mGluR5 as a target for Aβ oligomers (such as Renner at al., 2010), and Hamilton and colleagues had demonstrated that genetic deletion of mGluR5 alleviates AD phenotypes in mice (Hamilton at al., 2014). Most remarkable in their current study is the observation of beneficial effects in mice treated with CTEP starting at nine months of age. Beneficial effects of CTEP observed in behavioral assays can be potentially explained by synaptoprotective effects. Unfortunately analysis of synaptic loss was not performed by the authors. To explain reduction in amyloid plaques, the authors suggest that the reduction of AD pathology may occur as a consequence of reduced mGluR5-dependent APP translation, but this idea was not tested experimentally. Overall, this study further suggests the importance of synaptic calcium dysregulation in causing AD pathology and implicates mGluR5 as a therapeutic target.
References:
Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A. Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron. 2010 Jun 10;66(5):739-54. PubMed.
Hamilton A, Esseltine JL, DeVries RA, Cregan SP, Ferguson SS. Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer's disease. Mol Brain. 2014 May 29;7:40. PubMed.
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