申杰
,姚雪榕
,刘越存
,徐桂华.PDGFR-β/TGF-β/Smad2/3信号通路调控阿尔茨海默病血脑屏障完整性和学习记忆能力的分子机制研究[J].神经损伤功能重建,2024,(1):1-7 |
PDGFR-β/TGF-β/Smad2/3信号通路调控阿尔茨海默病血脑屏障完整性和学习记忆能力的分子机制研究 |
Regulatory Mechanism of Blood-brain Barrier Integrity and Learning and Memory Ability inAlzheimer's Disease via PDGFR-β/TGF-β/Smad2/3 Signal Pathway |
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DOI: |
中文关键词: 阿尔茨海默病 血小板源性生长因子受体β 转化生长因子-β 血脑屏障完整性 学习记忆能力 |
英文关键词: Alzheimer's disease platelet-derived growth factor receptor-beta transforming growth factor beta blood-brain barrier integrity learning and memory ability |
基金项目:国家自然科学基金
(血小板源性生长
因子受体-β在脑缺
血后血脑屏障修复
中 的 作 用 机 制 研
究,No. 81360186;
PDGFR-β/TGFβ/
Smad2/3 信号通路
在调控血脑屏障完
整性的分子机制研
究,No.81860228);
东莞市社会发展科
技项目(PDGFR-β/
TGF β/Smad2/3 信
号通路在调控阿尔
茨海默病血脑屏障
完整性和神经元保
护 的 分 子 机 制 研
究,No. 202118009
04462;基于格林模
式的健康教育在缺
血性脑卒中患者二
级预防的应用,No.
20211800900262;
二甲双胍对帕金森
合并糖尿病患者认
知功能的影响及其
机制,No. 2021180
0900492)、东莞市
滨海湾中心医院高
水平科研孵化基金
项目(脑缺血-再灌
注后星形胶质细胞
在调控血脑屏障功
能恢复和神经保护
的分子机制研究,
No. 2022001) |
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中文摘要: |
目的:分析PDGFR-β/TGF-β/Smad2/3信号通路调控阿尔茨海默病(AD)血脑屏障(BBB)完整性和学
习记忆能力的分子机制。方法:利用APP/PS1转基因AD小鼠模型,通过水迷路及觅食试验分析学习记忆能
力;荧光免疫组织化学法检测海马区血管周细胞增殖率(ki67/desmin)、周细胞覆盖率(desmin/lectin);Western blot检测海马区血管周细胞TGF-βR1及其下游信号通路分子、紧密连接(TJs)蛋白的表达水平。经过外源
性PDGF-BB脑室内注射和/或TGF-βR1激酶抑制剂SB431542腹腔内注射预处理后,分别进行上述分析。构
建 AD 体外 BBB 模型,经过 PDGF-BB 和/或 SB431542 作用后,进行异硫氰酸荧光素-牛血清白蛋白
(FITC-BSA)渗透性和跨细胞电阻检测。结果:与对照组相比,APP/PS1小鼠经过虚拟平台次数明显减少,达
到终点所需时间明显延长(水迷路训练试验),投食区正确选择率明显下降(觅食训练试验);海马区desmin/
lectin阳性细胞比例明显下降;TGF-βR1、p-Smad2、p-Smad3蛋白表达水平明显升高;TJs蛋白表达水平明显下
降。外源性PDGF-BB可使APP/PS1小鼠经过虚拟平台次数明显增加、达到终点所需时间明显缩短(水迷路正
式试验第28天)、投食区正确选择率明显提高(觅食正式试验第28天);海马区desmin/lectin阳性细胞比例明显
增加;使TGF-βR1、p-Smad2、p-Smad3蛋白表达水平明显升高;使TJs蛋白表达水平明显升高。SB431542则可
部分抑制上述作用。体外试验证明:外源性PDGF-BB可明显降低AD模型组的最终渗透系数,提高24 h时相
对TEER值;SB431542则可部分抑制上述作用。结论:PDGFR-β/TGF-β/Smad2/3信号通路可通过诱导周细
胞分化、覆盖,提高内皮细胞TJs的表达,调控AD血脑屏障完整性,以促进学习记忆能力恢复。 |
英文摘要: |
To investigate the molecular regulatory mechanism of integrity of blood-brain barrier
(BBB) and learning and memory ability in Alzheimer's disease (AD) via PDGFR-β/TGF-β/Smad2/3 signaling
pathway. Methods: Using the APP/PS1 transgenic mouse model of AD, the learning and memory abilities of
mice were analyzed through water maze test and food search test. The proliferation rate and pericyte coverage
rate in hippocampus were measured. The level of TGF-β R1 and its downstream signal pathway molecules, and
the levels of tight junctions (TJs) were analyzed. After intraventricular microinjection with exogenous PDGF-BB
and/or intraperitoneal injection with SB431542, the transgenic mice were analyzed by the above methods. After
PDGF-BB and/or SB431542 treatment, permeability and transcellular resistance were tested in the BBB model
in vitro. Results: Compared with the control group, APP/PS1 mice showed the learning and memory disability
in the water maze test and food search test, the less proportion of desmin/lectin positive cells in the
hippocampus, the lower levels of TGF-β R1, p-Smad2 and p-Smad3 protein, and the lower levels of TJs.
Furthermore, exogenous PDGF-BB could significantly enhance the learning and memory ability, increase the
pericyte coverage rate, raise the expression levels of TGF-β R1, p-Smad2 and p-Smad3 protein, and heighten the
expression levels of TJs proteins. In contrast, SB431542 could partially inhibit the above effects of PDGF-BB
treatment. In vitro tests showed that exogenous PDGF-BB could significantly reduce the final permeability
coefficient of AD model group and increase the relative TEER value at 24 h; SB431542 can partially inhibit the
above effects. Conclusion: PDGFR-β/TGF-β/Smad2/3 signal pathway may play a vital role in regulating the
integrity of blood-brain barrier and the recovery of learning and memory ability in AD. |
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