Hamilton Alison, Vasefi Maryam, Vander Tuin Cheryl, McQuaid Robyn J, Anisman Hymie, Ferguson Stephen S G
University of Ottawa Brain and Mind Institute, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
Robarts Research Institute, 100 Perth Drive, London, ON N6A 5K8, Canada.
Cell Rep. 2016 May 31;15(9):1859-65. doi: 10.1016/j.celrep.2016.04.077. Epub 2016 May 19.
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.
β-淀粉样蛋白（Aβ）寡聚体参与阿尔茨海默病（AD）的病理生理过程，且代谢型谷氨酸受体5（mGluR5）已被证明是Aβ寡聚体和细胞朊蛋白的受体。此外，在AD的APPswe/PS1ΔE9小鼠模型中，mGluR5的基因缺失可改善认知功能，并降低Aβ斑块和Aβ寡聚体浓度。在此，我们表明，长期口服生物可利用的mGluR5选择性负变构调节剂CTEP，其在结构、效力和选择性上与目前正处于治疗重度抑郁症和脆性X综合征II期临床开发阶段的巴辛格鲁特（RO4917523）相似，可逆转APPswe/PS1ΔE9小鼠的认知衰退，并降低APPswe/PS1ΔE9和3xTg-AD雄性小鼠的Aβ斑块沉积及可溶性Aβ寡聚体浓度。这些发现表明，CTEP或其类似物巴辛格鲁特可能是治疗AD患者的有效疗法。
