Cho Joshua D, Kim Yoon A, Rafikian Elizabeth E, Yang Mu, Santa-Maria Ismael
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, United States.
Department of Pathology & Cell Biology, Columbia University, New York, NY, United States.
Front Behav Neurosci. 2021 May 21;15:634157. doi: 10.3389/fnbeh.2021.634157. eCollection 2021.
Hyperphosphorylation and the subsequent aggregation of tau protein into neurofibrillary tangles (NFTs) are well-established neuropathological hallmarks of Alzheimer's disease (AD) and associated tauopathies. To further examine the impact and progression of human tau pathology in neurodegenerative contexts, the humanized tau (htau) mouse model was originally created. Despite AD-like tau pathological features recapitulated in the htau mouse model, robustness of behavioral phenotypes has not been fully established. With the ultimate goal of evaluating the htau mouse model as a candidate for testing AD therapeutics, we set out to verify, in-house, the presence of robust, replicable cognitive deficits in the htau mice. The present study shows behavioral data collected from a carefully curated battery of learning and memory tests. Here we report a significant short-term spatial memory deficit in aged htau mice, representing a novel finding in this model. However, we did not find salient impairments in long-term learning and memory previously reported in this mouse model. Here, we attempted to understand the discrepancies in the literature by highlighting the necessity of scrutinizing key procedural differences across studies. Reported cognitive deficits in the htau model may depend on task difficulty and other procedural details. While the htau mouse remains a unique and valuable animal model for replicating late onset AD-like human tau pathology, its cognitive deficits are modest under standard testing conditions. The overarching message is that before using any AD mouse model to evaluate treatment efficacies, it is imperative to first characterize and verify the presence of behavioral deficits in-house.
tau蛋白的过度磷酸化以及随后聚集成神经原纤维缠结（NFTs）是阿尔茨海默病（AD）及相关tau蛋白病公认的神经病理学特征。为了进一步研究人类tau蛋白病理在神经退行性疾病中的影响和进展，最初创建了人源化tau（htau）小鼠模型。尽管htau小鼠模型重现了类似AD的tau蛋白病理特征，但行为表型的稳健性尚未完全确立。为了最终将htau小鼠模型评估为测试AD治疗药物的候选模型，我们着手在内部验证htau小鼠是否存在稳健、可重复的认知缺陷。本研究展示了从精心策划的一系列学习和记忆测试中收集的行为数据。我们在此报告，老年htau小鼠存在显著的短期空间记忆缺陷，这是该模型中的一个新发现。然而，我们并未发现此前报道的该小鼠模型在长期学习和记忆方面有明显损伤。在此，我们试图通过强调仔细审查不同研究之间关键程序差异的必要性来理解文献中的差异。htau模型中报道的认知缺陷可能取决于任务难度和其他程序细节。虽然htau小鼠仍然是复制晚发型AD样人类tau蛋白病理的独特且有价值的动物模型，但其在标准测试条件下的认知缺陷并不明显。最重要的是，在使用任何AD小鼠模型评估治疗效果之前，必须首先在内部表征并验证行为缺陷的存在。
