高压氧通过调节BACE1蛋白水平改善APP/PS1模型小鼠Aβ相关病理改变及认知功能  

Hyperbaric oxygen therapy ameliorates Aβ-related pathological changes and cognitive function of APP/PS1 transgenic mice by reduction of BACE1

作　　者：邓青山 王东[1] 张超[1] 吴蛟 王翰[1] 邱俊[1] 陶裕川[1] 周世军[1] 易勇[1] DENG Qing-shan;WANG Dong;ZHANG Chao;WU Jiao;WANG Han;QIU Jun;TAO Yu-chuan;ZHOU Shi-jun;YI Yong(Department of Neurosurgery, Second People’s Hospital of Yibing City, Yibing 644000, China)

机构地区：[1]四川省宜宾市第二人民医院神经外科

出　　处：《中国病理生理杂志》2019年第7期1219-1225,共7页Chinese Journal of Pathophysiology

摘　　要：目的:探索高压氧(HBO)治疗对阿尔茨海默病APP/PS1转基因(TG)小鼠脑β-淀粉样蛋白(Aβ)相关病理改变及认知障碍的治疗作用。方法:取4月龄的APP/PS1转基因小鼠30只随机分为2组(TG组和TG+HBO组),野生对照小鼠15只(WT组),分别进行高压氧治疗和对照治疗6个疗程。治疗结束后用水迷宫实验检测各组小鼠认知功能;取小鼠脑标本进行免疫荧光检测小鼠脑老年斑表达情况;高尔基染色检测树突棘密度;通过酶联免疫吸附实验检测Aβ40和Aβ42的水平;Western blot法检测Sirt1、BACE1、APP、α/β-CTF和synaptophysin的蛋白表达水平。结果:与TG组相比,高压氧治疗能减少TG+HBO组小鼠脑中Aβ的产生和老年斑的形成(P<0.01);与TG组相比,高压氧治疗能增加TG+HBO组小鼠脑中Sirt1的蛋白水平,降低BACE1的蛋白水平,从而减少β-CTF的产生(P<0.01);与TG组相比,HBO治疗能增加TG+HBO组小鼠脑神经棘突数量与synaptophysin蛋白水平(P<0.01),从而明显改善APP/PS1转基因小鼠的学习记忆功能。结论:高压氧治疗能通过增加Sirt1蛋白表达、降低BACE1蛋白水平而减少APP裂解产生Aβ及老年斑形成,进而减轻Aβ的神经毒性损伤,最终发挥神经保护作用。AIM: To explore the neuroprotective effects of hyperbaric oxygen(HBO) therapy on the brain of APP/PS1 transgenic(TG) mice. METHODS: Four-month-old APP/PS1 transgenic mice and the wild-type(WT) littermates were randomly divided into 3 groups: TG+HBO, TG, and WT. All mice were administrated with HBO or control treatment for 6 cycles. The animals were subjected to Morris water maze. The mice were killed and the brains were collec-ted for coronal section and other biochemical analysis. The brain sections were subjected to immunofluorescence staining for observing the amyloid plaques. The levels of Aβ40 and Aβ42 were measured by ELISA. The protein levels of Sirt1, BACE1, APP,α/β-CTF and synaptophysin were determined by Western blot. RESULTS: In TG+HBO group, HBO treatment reduced Aβ generation and plaque formation in the brains as compared with TG group(P<0.01). HBO treatment also increased the protein level of Sirt1, but reduced the protein level of BACE1 and the cleavage of APP by BACE1(P<0.01). HBO treatment attenuated the loss of spines and synapses, thus rescuing the learning and memory deficits in APP/PS1 mice. CONCLUSION: HBO treatment rescues cognitive deficits of APP/PS1 transgenic mice by increasing the level of Sirt1 and reducing the level of BACE1 protein, thus reducing the generation of Aβ and its neurotoxicity in APP/PS1 transgenic mice.

关 键 词：阿尔茨海默病 高压氧治疗 BACE1蛋白 认知障碍 

分 类 号：R749.1[医药卫生—神经病学与精神病学] R363.2[医药卫生—临床医学]