AβPPLon/Swe转基因小鼠记忆缺陷逆转与甲醛水平降低相关
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1.2)中国科学院生物物理研究所脑与认知国家重点实验室,北京100101;2.4) Biomedicine Discovery Institute, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne 3800, Australia;3.1) 北京中医药大学生命科学学院,北京 102488;4.3)中国科学院大学,北京100049;5) 巴彦淖尔市医院,巴彦淖尔 015000;6.2) 中国科学院生物物理研究所脑与认知国家重点实验室,北京 100101

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中央高校基本科研业务费专项资金(2020-JYB-ZDGG-051),科技部国家重点基础研究发展计划(2012CB911004)和内蒙古自治区自然科学基金(2021MS08040)资助项目.


Reversal of Memory Deficit Correlates to Formaldehyde Reduction in AβPPLon/Swe Mice
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1.2)State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academey of Sciences, Beijing 100101, China;2.4)Biomedicine Discovery Institute, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne 3800, Australia;3.1) School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China;4.3)University of Chinese Academy of Sciences, Beijing 100049, China;5.4) Biomedicine Discovery Institute, Faculty of Medicine, Nursing & Health Sciences, Monash University, Melbourne 3800, Australia;6.5)Bayannur Hospital, Bayannur, Inner Mongolia Autonomous Region 015000, China;7.2) State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academey of Sciences, Beijing 100101, China

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This work was supported by grants from the Fundamental Research Funds for the Central Universities (2020-JYB-ZDGG-051), the National Basic Research Program of China (2012CB911004) and Natural Science Foundation of Inner Mongolia Autonomous Region (2021MS08040).

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    摘要:

    β淀粉样蛋白(Aβ)沉积形成斑块是阿尔茨海默病(AD)的病理标志之一. 以β淀粉样前体蛋白(AβPP)为基础的转基因小鼠模型表现出斑块形成加速和记忆损伤. 然而,在一些模型中,记忆丧失与斑块形成的相关性较差. 我们实验室最近报道了AD患者和动物模型的认知障碍与其体内甲醛水平有很强的相关性. 本研究发现,AβPPLon/Swe转基因小鼠3月龄时表现出记忆缺陷,而在6月龄时记忆正常,其工作记忆与甲醛水平变化相反. 与对照组相比,3月龄小鼠记忆受损伴随着甲醛水平的增高和过度磷酸化tau的增加. 腹腔注射甲醛清除剂白藜芦醇可通过降低甲醛水平和tau蛋白的过度磷酸化,挽回小鼠的记忆损伤. 6月龄AβPPLon/Swe小鼠甲醛水平和工作记忆与对照组相似,伴随甲醛降解酶ALDH2和ADH3表达增加. 结果显示,在AβPPLon/Swe转基因小鼠中,大脑甲醛水平与记忆变化进程显著相关,且记忆的恢复与甲醛水平下降相关. 该研究为揭示阿尔茨海默病机制研究提供了新视角.

    Abstract:

    The formation of plaques by the deposition of amyloid-β (Aβ) in the brain is a hallmark of Alzheimer’s disease (AD). Transgenic mouse models based on amyloid-β precursor protein (AβPP) exhibited accelerated plaque formation and memory impairment. However, in some models, the correlation between memory loss and plaque formation is poor. Our lab has recently found a strong correlation between formaldehyde levels and cognitive impairment in AD patients and animal models. In the present study, we found that working memory was inversely correlated with formaldehyde levels in AβPPLon/Swe transgenic mice, which showed memory deficiency at 3 months of age but normal memory at 6 months. Impaired memory in 3-month-old mice was accompanied by higher levels of formaldehyde and hyperphosphorylated tau than controls. Administration of resveratrol, which is a formaldehyde scavenger, rescued the cognitive deficits in these mice by reducing formaldehyde levels and attenuating tau hyperphosphorylation. With increased expression of formaldehyde catalytic enzymes such as aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase III (ADH3), 6-month-old AβPPLon/Swe mice displayed similar levels of formaldehyde and working memory as controls. We discovered that brain formaldehyde levels were significantly associated with the progression of memory deficit in AβPPLon/Swe transgenic mice, and that recovery of memory was associated with formaldehyde reduction. Our findings provide valuable insights into the underlying mechanisms of AD.

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卢静,何欢,苗君叶,朱岩,李婷,陈茜茜,童志前,赫荣乔,刘缨. AβPPLon/Swe转基因小鼠记忆缺陷逆转与甲醛水平降低相关[J].生物化学与生物物理进展,2021,48(11):1337-1347

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历史
  • 收稿日期:2020-11-11
  • 最后修改日期:2021-04-05
  • 接受日期:2021-04-25
  • 在线发布日期: 2021-11-23
  • 出版日期: 2021-11-20