Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Research and Development, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Neurosci Lett. 2023 Feb 16;797:137080. doi: 10.1016/j.neulet.2023.137080. Epub 2023 Jan 16.
Tauopathies are a heterogeneous group of neurodegenerative disorders that are clinically and pathologically distinct from Alzheimer's disease (AD) having tau inclusions in neurons and/or glia as their most prominent neuropathological feature. BCI-838 (MGS00210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APP) transgenic mice, a model of the pathological accumulation of Aβ oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPT associated with human frontotemporal lobar degeneration (FTLD). These mice develop an aging-related tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle, (2) PS19 mice treated with vehicle and (3) PS19 mice treated with 5 mg/kg BCI-838. Groups of 10-13 mice were utilized. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Behavioral testing consisting of a novel object recognition task was conducted after drug administration. Two studies were performed beginning treatment of mice at 3 or 7 months of age. One month of BCI-838 treatment rescued deficits in recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as their underlying basis. They also suggest an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice.
tau 病是一组神经退行性疾病，在临床上和病理学上与阿尔茨海默病（AD）不同，其神经元和/或神经胶质细胞中存在 tau 包含物，是其最突出的神经病理学特征。BCI-838（MGS00210）是 II 型代谢型谷氨酸受体（mGluR2/3）拮抗剂前药。此前，我们报道口服给予 BCI-838 可改善荷兰（APP）转基因小鼠的学习行为并减轻焦虑，荷兰转基因小鼠是 AD 中发现的 Aβ 寡聚物病理性积累的模型。在此，我们研究了 BCI-838 对表达与人类额颞叶变性（FTLD）相关的 tau 病突变 MAPT 的 PS19 雄性小鼠的影响。这些小鼠会出现与年龄相关的 tau 病，但没有淀粉样蛋白积累。将小鼠分为三组实验组：（1）未转基因野生型小鼠用载体处理，（2）PS19 小鼠用载体处理，（3）PS19 小鼠用 5mg/kg BCI-838 处理。每组使用 10-13 只小鼠。用口服灌胃的方式给予载体或 BCI-838 治疗 4 周。在给药后进行新物体识别任务的行为测试。两项研究从 3 或 7 个月龄开始治疗小鼠。一个月的 BCI-838 治疗挽救了 PS19 小鼠的识别记忆缺陷，无论治疗是从 3 个月还是 7 个月龄开始。这些研究将 BCI-838 的潜在用途扩展到以 tau 病为基础的神经退行性疾病。它们还表明 mGluR2/3 依赖性机制是 PS19 小鼠行为缺陷的基础。
