细胞凋亡与神经损伤修复.ppt

Selective Neuronal Losses in Neurodegenerative Diseases 1. Death of hippocampal and cortical neurons in AD 2. Death of midbrain dopaminergic neurons in PD 3. Death of neurons in the striatum that control body movements in HD 4. Death of spinal motor neurons in ALS Alzheimer’s Disease (AD)  Thank you! Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology Bradley T. Hyman Junying Yuan Nature Reviews Neuroscience?13,?395-406?(June 2012) Apoptosis in the nervous system Nature?407, 802-809 (12 October 2000) |?doi:10.1038Junying Yuan? Bruce A. Yankner * * * * Apoptotic protease-activating factor 1 Pro-apoptotic proteins: EGL-1, Bik, Bax 2.Possible mechanisms of action of Bcl-2 family members a. Formation of a pore, through which cytochrome c (Cyt c) and other intermembrane proteins can escape. b. Heterodimerization between pro- and anti-apoptotic family members. Pro-apoptotic Bax... c. Direct regulation of caspases via adaptor molecules, as has been described in C. elegans. d. interact with other mitochondrial protein VDAC: voltage-dependent anion channel ANT: adenosine nucleotide transpoter e. Oligomerization to form a weakly selective ion channel Formation of a pore Heterodimerization Direct regulation of caspases via adaptor molecules interact with other mitochondrial protein Oligomerization to form a weakly selective ion channel 3. Bcl-2家族与神经元凋亡 Bcl-2在发育的CNS中表达水平较高，出生后下降 体外培养的条件下，过度表达bcl-2，对NGF、NT-3、BDNF剥夺导致的神经元凋亡有抑制作用 体内转基因动物，过度表达bcl-2的小鼠，脑神经元数量增加，并且对神经轴突离断诱导的死亡有抑制作用 Bcl-2缺乏鼠，小鼠发育正常，但是E14三叉神经节细胞死亡比例明显增高，在E16-E18阶段，细胞数量较正常对照明显减少，且感觉、运动和交感神经元在出生后明显减少。表明Bcl-2对神经元存活是非常重要的 Bcl-xL Bcl-xL 缺乏鼠在胚胎第13天死亡，神经系统中大量的细胞死亡。主要发生在未形成突触联系的非成熟神经元。 Bcl-xL可能在神经元与其靶细胞建立突触联系中起重要作用。 Bax是在神经系统中广泛表达的促凋亡因子； Bax缺乏鼠颈上神经节和面神经核神经元数量增加， 新生的交感神经元对NGF剥夺和神经轴突离断抗 性增加 神经营养因子withdraw可以激活Bax，进而导致神 经元凋亡 Bax （三）线粒体与细胞凋亡 通过四种方式影响细胞的生存与死亡 细胞呼吸链受损，ATP减少 是ROS的主来源之一。 ROS 信使分子与效应分子，凋亡刺激，ROS增加 线粒体膜电位降低