Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau
Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau
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DOI：
10.1186/s13195-019-0522-z
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发表时间：
2019-08-01
影响因子：
9
通讯作者：
Rominger, Axel
中科院分区：
文献类型：
--
作者：
Brendel, Matthias;Deussing, Maximilian;Rominger, Axel
背景用小分子调节剂增强毒性寡聚体的脑清除构成了对抗tau沉积的有前景的治疗概念。然而，还没有在阿尔茨海默病（AD）的动物模型中测试这一概念，其起始于疾病晚期。因此，我们的目的是研究干预性晚期Anle 138 b治疗的效果，该治疗先前表明通过结合病理性聚集体来抑制寡聚体积累的巨大潜力，在一项纵向F-18-氟脱氧葡萄糖正电子发射断层扫描（FDG-PET）研究中，10名对照组在基线（14.5个月）时通过FDG-PET成像，随后随机分为Anle 138b治疗组和载体组，持续3个月。治疗3个月后重复FDG-PET，并通过tau免疫组织化学分析大脑。比较研究组之间葡萄糖代谢的纵向变化，终点Tau负荷与个体FDG-PET结果相关。
BackgroundAugmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) study.MethodsTwelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5months), followed by randomization into Anle138b treatment and vehicle groups for 3months. FDG-PET was repeated after treatment for 3months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings.ResultsTau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex -53%, p