Laboratory of Neurobiophysics, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan.
Brain Res. 2021 Aug 15;1765:147496. doi: 10.1016/j.brainres.2021.147496. Epub 2021 Apr 22.
Insoluble, fibrillar intraneuronal accumulation of the tau protein termed neurofibrillary tangles (NFTs), are characteristic hallmarks of Alzheimer's disease (AD). They play a significant role in the behavioral phenotypes of AD. Certain mice (rTg4510) constitutively express mutant human tau until transgene expression is inactivated by the administration of doxycycline (DOX). The present study aimed to determine the timing of the onset of memory impairment in rTg4510 mice and define the relationship between the extent of memory deficit and the duration of NFT overexpression. In 6-month-old (young) rTg4510 mice, both spatial memory and object recognition memory were impaired. These impairments were prevented by pre-treatment with DOX for 2 months. In parallel, the expression of NFTs decreased in the DOX-treated group. Ten-month-old (aged) rTg4510 mice showed severe impairments in memory performance. Pretreatment with DOX did not prevent these impairments. Increasing levels of NFTs were observed in aged rTg4510 mice. DOX treatment did not prevent tau pathology in aged rTg4510 mice. Expression of the autophagy markers LC3A and LC3B increased in rTg4510 mice, along with an increase in NFT formation. These results suggest that the clearance mechanisms of NFTs are impaired at 10 months of age.
不溶性、纤维状的神经元内tau 蛋白积累称为神经原纤维缠结 (NFTs)，是阿尔茨海默病 (AD) 的特征性标志。它们在 AD 的行为表型中起着重要作用。某些小鼠 (rTg4510) 持续表达突变型人类 tau，直到通过给予强力霉素 (DOX) 使转基因表达失活。本研究旨在确定 rTg4510 小鼠记忆障碍的发病时间，并确定记忆缺陷的严重程度与 NFT 过度表达持续时间之间的关系。在 6 个月大的 (年轻) rTg4510 小鼠中，空间记忆和物体识别记忆受损。用 DOX 预处理 2 个月可预防这些损伤。同时，DOX 处理组中 NFT 的表达减少。10 个月大的 (年老) rTg4510 小鼠表现出严重的记忆障碍。用 DOX 预处理不能预防这些损伤。在年老的 rTg4510 小鼠中观察到 NFT 水平升高。DOX 处理不能预防年老的 rTg4510 小鼠中的 tau 病理学。自噬标志物 LC3A 和 LC3B 在 rTg4510 小鼠中的表达增加，同时 NFT 形成增加。这些结果表明，在 10 个月大时，NFT 的清除机制受损。
