Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer's disease: a preclinical study in rTg4510 mice
Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer's disease: a preclinical study in rTg4510 mice
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DOI：
10.1186/s13195-019-0530-z
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发表时间：
2019-08-23
影响因子：
9
通讯作者：
Lin, Chien-Liang Glenn
中科院分区：
文献类型：
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作者：
Foster, Joshua B.;Lashley, Rashelle;Lin, Chien-Liang Glenn
背景阿尔茨海默病（AD）缺乏有效的治疗方案是一个重大的社会问题。突触丧失是AD的标志，与记忆受损最相关，并且在疾病过程的早期，在临床症状发作之前发生。我们已经开发了一个小分子，哒嗪为基础的系列，提高了结构和功能的胶质过程和突触终扣，形成三方突触。以前，我们已经表明，这些哒嗪衍生物在淀粉样前体蛋白AD模型中表现出深刻的疗效。在此，我们评估了一种先进化合物LDN/OSU-0215111在rTg 4510小鼠（一种侵袭性tau蛋白病模型）中的疗效。方法rTg 4510小鼠从早期症状阶段（2月龄）至中度（4月龄）和重度（8月龄）疾病阶段每天口服溶剂或LDN/OSU-0215111（10 mg/kg）。在每个时间点，对小鼠进行一系列行为测试以评估活动水平和认知。此外，对一组小鼠进行组织收集，以分析通过免疫组织化学和蛋白质印迹评估的三重突触变化、神经变性、神经胶质增生和tau磷酸化。在8月龄时，将用化合物处理的rTg 4510小鼠的子集转换为媒介物处理，并在处理停止后30天进行行为和生化分析。结果在中度和重度疾病阶段，化合物治疗使认知和行为正常化，并减少突触丢失、神经变性、tau蛋白过度磷酸化和神经炎症。重要的是，在治疗停止30天后，化合物治疗的益处持续存在，表明疾病得到改善。我们还发现，化合物处理可能通过抑制GSK 3 β快速且稳健地减少tau过度磷酸化/沉积。结果表明，LDN/OSU-0215111为阿尔茨海默病中发现的tau蛋白病依赖性病理学的多个方面提供益处，包括三重突触正常化和毒性tau负荷的减少，这反过来可能解释了化合物处理的rTg 4510小鼠中正常化的认知和活动水平。这项研究，结合我们以前的工作，关于哒嗪衍生物对淀粉样蛋白依赖性病理学的好处，强烈支持哒嗪衍生物作为一个可行的，临床相关的，和疾病修饰治疗阿尔茨海默病的许多方面。
Background The lack of effective treatment options for Alzheimer's disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice-an aggressive tauopathy model. Methods rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation. Results At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3 beta. Conclusions The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer's disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer's disease.