AβPP^(Lon/Swe)转基因小鼠记忆缺陷逆转与甲醛水平降低相关  

Reversal of Memory Deficit Correlates to Formaldehyde Reduction in AβPP^(Lon/Swe)MiceReversal of Memory Deficit Correlates to Formaldehyde Reduction in AβPP^(Lon/Swe)Mice

作　　者：卢静[2,4] 何欢 苗君叶 朱岩[4] 李婷 陈茜茜 童志前 赫荣乔[2,3] 刘缨 LU Jing;HE Huan;MIAO Jun-Ye;ZHU Yan;LI Ting;CHEN Xi-Xi;TONG Zhi-Qian;HE Rong-Qiao;LIU Ying(School of Life Sciences,Beijing University of Chinese Medicine,Beijing 102488,China;State Key Laboratory of Brain and Cognitive Science,Institute of Biophysics,Chinese Academey of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China;Biomedicine Discovery Institute,Faculty of Medicine,Nursing&Health Sciences,Monash University,Melbourne 3800,Australia;Bayannur Hospital,Bayannur,Inner Mongolia Autonomous Region 015000,China)

机构地区：[1]北京中医药大学生命科学学院,北京102488 [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 [3]中国科学院大学,北京100049 [4]Biomedicine Discovery Institute,Faculty of Medicine,Nursing&Health Sciences,Monash University,Melbourne 3800,Australia [5]巴彦淖尔市医院,巴彦淖尔015000

出　　处：《生物化学与生物物理进展》2021年第11期1337-1347,共11页Progress In Biochemistry and Biophysics

基　　金：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);内蒙古自治区自然科学基金(2021MS08040)资助项目.

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,AβPP^(Lon/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AβPP^(Lon/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AβPP^(Lon/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.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-βprecursor 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 AβPP^(Lon/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 AβPP^(Lon/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 AβPP^(Lon/Swe)transgenic mice,and that recovery of memory was associated with formaldehyde reduction.Our findings provide valuable insights into the underlying mechanisms of AD.

关 键 词：甲醛 白藜芦醇 阿尔茨海默病 淀粉样前体蛋白 London/Swedish突变 水迷宫 

分 类 号：Q189[生物学—神经生物学] Q5[生物学—普通生物学]