通过患者衍生的脑和粉样β蛋白质的快速可逆持续的长期潜能抑制
Tomas Ondrejcak1, Igor Klyubin1, Neng-Wei Hu1,2
1Department of Pharmacology and Therapeutics, School of Medicine, and Institute of Neuroscience, Trinity College , Dublin 2, Republic of Ireland.
概括
突触毒性陶蛋白和粉样β蛋白在阿尔茨海默氏症 (AD) 中破坏突触可塑性. 患者衍生的持续数周,但可以通过抗抗体逆转.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 病理学 病理学 病理学
背景情况:
- 阿尔茨海默氏病 (AD) 的发病过程涉及粉样β (Aß) 和蛋白.
- 由于Aß和tau导致突触失效的确切机制尚未完全理解.
- 突触可塑性,特别是长期强化 (LTP),对记忆和学习至关重要.
研究的目的:
- 为了研究早期粉样性粉症对的破坏性影响对突触功能的影响.
- 为了确定各种突触毒性制剂对LTP抑制的持久性.
- 探索抗tau抗体对抗持续的tau神经毒性的治疗潜力.
主要方法:
- 在大鼠中用脑内注射重组的人类陶聚合物 (SτAs,oTau) 和来自患者的大脑提取物 (AD,皮克病).
- 评估了对海马长期潜能 (LTP) 的急性和持续影响.
- 利用转基因大鼠的粉样蛋白前体蛋白 (APP) 来建模早期粉样性病.
- 研究了抗tau单克隆抗体在逆转tau诱导的LTP抑制中的有效性.
主要成果:
- 单次注射复合聚合物 (SτAs,oTau) 在大鼠海马中迅速和持续抑制了LTP.
- 在APP转基因大鼠中,oTau的抑制作用的值降低了,这表明与粉样性粉症的相互作用.
- 来自AD和Pick病的大脑提取物中的synaptotoxic tau抑制了LTP超过两周.
- 来自患者的tau诱导的突触可塑性的持续性破坏被反tau单克隆抗体迅速逆转.
结论:
- 来自患者的突触毒性tau物种在大脑中持续数周,保持神经活性.
- 这些tau物种可以与粉样β (Aß) 一起作用,破坏突触可塑性.
- 反tau单克隆抗体显示出在神经退行性疾病中逆转持续的tau介导突触功能障碍的前景.
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