促红细胞生成素衍生肽治疗可减轻tau蛋白病小鼠模型的神经功能缺损和神经病理变化。
Erythropoietin-derived peptide treatment reduced neurological deficit and neuropathological changes in a mouse model of tauopathy.
作者信息
Choi Yun-Beom, Dunn-Meynell Ambrose A, Marchese Michelle, Blumberg Benjamin M, Gaindh Deeya, Dowling Peter C, Lu Wei
机构信息
Neurology Service, VA New Jersey Health Care System and Department of Neurology, Rutgers New Jersey Medical School, 385 Tremont Ave., East Orange, NJ, 07018, USA.
Neurology Service, VA New Jersey Health Care System and Department of Pharmacology, Physiology, and Neuroscience, Rutgers New Jersey Medical School, 385 Tremont Ave., East Orange, NJ, 07018, USA.
出版信息
Alzheimers Res Ther. 2021 Jan 27;13(1):32. doi: 10.1186/s13195-020-00766-4.
BACKGROUND
Prominent activation of microglial immune/inflammatory processes is a characteristic feature of brains of patients with tauopathies including Alzheimer's disease (AD), suggesting that neuroinflammation may be a critical factor in their pathogenesis. Strategies aimed at developing new therapeutics for tauopathies based on anti-inflammation or immunomodulation are likely to be promising avenues of research. We previously developed JM4-a 19'mer cyclic peptide derived from the first loop of human erythropoietin. This peptide possesses beneficial immune modulatory and tissue protective effects while lacking the undesirable side effects of full-length erythropoietin. In this preclinical study, we investigated the effect of chronic JM4 treatment on the PS19 mouse that carries the P301S mutant human tau gene, linked to a form of frontotemporal dementia. This transgenic mouse has been widely used as a model of tauopathies including AD and related dementias.
METHODS
Daily subcutaneous treatment of female PS19 mice with JM4 was initiated before disease onset and continued on for the animals' lifespan. The progression of neurological deficit and the lifespan of these mice were assessed. To evaluate the effect of JM4 treatment on cognition of these animals, the PS19 mice underwent Barnes maze test and elevated plus maze test. In addition, neuronal loss, phosphorylated tau aggregation, and microglial activation were assessed using immunohistochemistry of PS19 mouse brain sections.
RESULTS
JM4 treatment of PS19 mice initiated before disease onset reduced neurological deficit, prolonged lifespan, and rescued memory impairment. The beneficial effects of JM4 were accompanied by reductions in neuronal loss, phosphorylated tau aggregation, and microglial activation in the PS19 mouse brain.
LIMITATIONS
Use of a single dose of JM4 and female mice only.
CONCLUSION
JM4 is a potential novel therapeutic agent for the treatment of tauopathies including AD and related dementias.
背景
小胶质细胞免疫/炎症过程的显著激活是包括阿尔茨海默病（AD）在内的tau蛋白病患者大脑的一个特征，这表明神经炎症可能是其发病机制中的一个关键因素。基于抗炎或免疫调节开发tau蛋白病新疗法的策略可能是很有前景的研究途径。我们之前开发了JM4——一种源自人促红细胞生成素第一环的19肽环肽。这种肽具有有益的免疫调节和组织保护作用，同时没有全长促红细胞生成素的不良副作用。在这项临床前研究中，我们研究了慢性JM4治疗对携带与一种额颞叶痴呆形式相关的P301S突变型人tau基因的PS19小鼠的影响。这种转基因小鼠已被广泛用作包括AD和相关痴呆在内的tau蛋白病模型。
方法
在疾病发作前开始对雌性PS19小鼠每日皮下注射JM4，并持续至动物寿命结束。评估这些小鼠神经功能缺损的进展和寿命。为了评估JM4治疗对这些动物认知的影响，PS19小鼠接受了巴恩斯迷宫试验和高架十字迷宫试验。此外，使用PS19小鼠脑切片的免疫组织化学评估神经元丢失、磷酸化tau蛋白聚集和小胶质细胞激活。
结果
在疾病发作前开始用JM4治疗PS19小鼠可减少神经功能缺损、延长寿命并挽救记忆障碍。JM4的有益作用伴随着PS19小鼠大脑中神经元丢失、磷酸化tau蛋白聚集和小胶质细胞激活的减少。
局限性
仅使用单剂量的JM4且仅使用雌性小鼠。
结论
JM4是一种潜在的新型治疗药物，可用于治疗包括AD和相关痴呆在内的tau蛋白病。
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