Beta-amyloid (Aβ) oligomers contribute to the pathophysiology of Alzheimer disease (AD), and metabotropic glutamate receptor 5 (mGluR5) has been shown to act as a receptor for both Aβ oligomers and cellular prion proteins. Furthermore, the genetic deletion of mGluR5 in an APPswe/PS1δE9 mouse model of AD improves cognitive function and reduces Aβ plaques and Aβ oligomer concentrations. Here, we show that chronic administration of the orally bioavailable mGluR5-selective negative allosteric modulator CTEP, which is similar in structure, potency, and selectivity to Basimglurant (RO4917523), which is currently in phase II clinical development for major depressive disorder and fragile X syndrome, reverses cognitive decline in APPswe/PS1δE9 mice and reduces Aβ plaque deposition and soluble Aβ oligomer concentrations in both APPswe/PS1δE9 and 3xTg-AD male mice. These findings suggest that CTEP or its analogue Basimglutant might potentially be an effective therapeutic for the treatment of AD patients.

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Persistent URL dx.doi.org/10.1016/j.celrep.2016.04.077
Journal Cell Reports
Citation
Hamilton, A. (Alison), Vasefi, M. (Maryam), Vander Tuin, C. (Cheryl), McQuaid, R.J. (Robyn J.), Anisman, H, & Ferguson, S.S.G. (Stephen S.G.). (2016). Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model. Cell Reports, 15(9), 1859–1865. doi:10.1016/j.celrep.2016.04.077