Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model
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.
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