暑期实践口头报告会： 9月27 日，报告厅 Oral presentation ppt file Written report file 请将以上2个文件在 9月21日下午5： 00前传至：孙夏琴： 10811017@pku. edu. cn 62754880
Oral Presentation Skills Scientific ideas are what you sell Modified from Samuel B. Silverstein, Dept. Physics, Stockholm University
Your audience are trapped to your talk So take good care of them Interact with your audience Look at your audience Keep eye contact with your audience Watch the body language of your audience
Summary and Conclusions Implication of caspase-6 in human neuronal cell death First direct evidence showing caspase-6 (but not caspase-3) is the key player in human neuronal cell death and may be involved in AD development. Human = Talking mouse Inhibition of caspase-6 in human neuronal cell death First identification of caspase inhibitory factor (CIF), the only natural inhibitor to active caspase-6, induced by 17 - -estradiol at physiological concentrations. Supporting evidence that both estrogen androgens can be potential candidates for early anti-amyloid therapy for AD. Structural integrity = Functional integrity
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Caspase-6 activation is involved in intracellular A 1 -42 toxicity * p<0. 01
Caspase-6 induces neuronal cell death in a dosedependent manner 90 25 ** 5 30 20 ** Injection of denatured recombinant caspase-6 (100 pg csp 6/neuron) 0 4 8 Time (days) ** 16 ** ** pa s ca s DM 40 ** ** 15 SO 50 % Neuronal Cell Death 60 35 100 80 60 40 20 0 BO e-6 CDfm ZVA k Dfm ZVE k ID -f ZDE mk VD -fm ZIE k TD -fm k 70 ** p<0. 01 * p<0. 05 ** ** ** 10 pg R-Csp-6/cell 100 50 20 10 0. 5 0. 25 0. 01 0. 1 5 0 0 % Neuronal Cell Death 80 % Neuronal Cell Death 45 Stau
100 80 20 0 5 10 15 Time (days) 20 52 K 100 caspase-3 caspase-6 caspase-7 caspase-8 80 60 40 20 0 0 5 10 15 Time (days) 116 K 20 actin NAIP 40 c. IAP 2 60 0 % Astrocytic Cell Death caspase-3 caspase-6 caspase-7 caspase-8 c. IAP 1 % Neuronal Cell Death Different sensitivities to caspases in human neurons and astrocytes
ER activity is measured by Luciferase reporter system ER Estrogen responsive element reporter (firefly luciferase) Lower or abolish of luciferase activity ER+dominant negative ER constructs DBD PM Nucleus Estrogen Endogenous ER X Mutant ER Luciferase activity Thymidine Kinase (promoter) ERE Luc reporter (firefly) (promoter) Transfection efficiency Luc reporter (renilla) X ERE Luc reporter (firefly) (promoter) Luciferase activity=(firefly/renilla) *10, 000
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Caspase-6 may be involved in human neuronal cell death Caspase-6, but not caspase-3, -7 or – 8, is activated during serum deprivation-induced human neuronal cell death (Le. Blanc et al. , 1999). Caspase-6 specific inhibitor can block apoptosis in human neurons (Le. Blanc et al. , 1999). Caspase-6 inhibitor can block apoptotic promoting effects of APPBP 1, an APP binding protein (Chen et al. , 2000). Active caspase-6 p 10 fragments may increase in AD brains (Le. Blanc et al. , 1999). Caspase-6 can cleave APP directly, which may be a pathway to increase A production (Le. Blanc et al. , 1999; Pellegrini et al. , 1999).
Implication and Inhibition of Caspase-6 in Human Neuronal Cell Death Yan Zhang Department of Neurology and Neurosurgery Mc. Gill University
Summary and Conclusions Implication of caspase-6 in human neuronal cell death First direct evidence showing caspase-6 (but not caspase-3) is the key player in human neuronal cell death and may be involved in AD development. Human = Talking mouse Inhibition of caspase-6 in human neuronal cell death First identification of caspase inhibitory factor (CIF), the only natural inhibitor to active caspase-6, induced by 17 - -estradiol at physiological concentrations. Supporting evidence that both estrogen androgens can be potential candidates for early anti-amyloid therapy for AD. Structural integrity = Functional integrity
Acknowledgements Dr. Andréa C. Le. Blanc Alzheimer Society Canada for “Doctoral Training Award” Dr. Stefano Stifani Dr. Bernard Turcotte Dr. Heather Durham Dr. Judes Poirier Dr. Antonis Koromilas Dr. Mark Trifiro Dr. Lenore Beitel Dr. Sylvie Mader Dr. Cynthia Goodyer Dr. Nathalie Champagne Dr. Lina Musallam Dr. Xavier Roucou Dr. Omar Tounekti Dr. Malcolm Gains Jennifer Hammond Megan Blacker Tracy Petzke Qi Guo Huishan Guo Nicole Quenneville Beverly Akerman Guy Klaiman Younes Bounhar
Androgen (testosterone and methyl-testosterone) AR Genomic pathway Transcriptional regulation of responsive genes Other survival pathways Intracellular A 1 -42 p 53 phosphorylation Upregulate Bax Activate caspase-6 CIF? Cell death Signal transduction pathway Cellular ER Estrogen (17 - -estradiol)
a. 对突触AMPA受体的特性、亚基组成和运输的改变 （1）AMPA受体的亚基组成的调节作用 1. 在成熟的海马组织中，AMPA受体主要由Glu. R 1/Glu. R 2组成，其次是 Glu. R 3/Glu. R 2。 2. Glu. R 2对AMPA受体有着多种调节作用：Glu. R 2 -lacking AMPAR有着 高度的Ca的通透性，高的通道电导，高的开放几率，和整流能力（ rectification, 内源的细胞内多胺与其相互作用）。所以受体组成对突触传导有 重要的调节作用。 （2）AMPA受体亚基磷酸化的调节作用：直接改变受体特性，或者作为一个 readout，与突触可塑性和学习有关的信号通路联系起来。 1. 缺少Glu. R 1的831位和845位氨基酸（两个重要的磷酸化位点）的小 鼠不能建立ＬＴＤ和ＬＴＰ，并且有空间学习能力的障碍。 2. Ca. MKII磷酸化Glu. R 1的831位丝氨酸，能极大提高同聚Glu. R 1型 AMPAR的单通道电导。在海马CA 1区表达Ca. MKII的组成激活型，可以提高 AMPAR的单通道电导。而AMPAR单通道电导的提高在ＬＴＰ时发生。所以 被认为是早期ＬＴＰ的机制。 3. PKA对Glu. R 1的845位丝氨酸磷酸化，能提高同聚Glu. R 1型AMPAR 的开放频率。 （3）AMPA受体运输的调节作用: AMPAR在突触膜上的密度受到动态的插膜 和内化的调节。静息时，Glu. R 2/Glu. R 3型AMPAR有组成性循环。Ca通过 NMDAR的内流是受体循环的重要调节信号。Glu. R 1似乎对ＬＴＰ期AMPAR的 插膜调节有关；Glu. R 2似乎对LＴＤ期AMPAR的内化有关。
AMPA受体运输（AMPA receptor trafficking）是一个有趣的研究领域。1998年 Neuron上首次报道AMPA受体总是处于迅速的插膜和内化的循环中。突触后膜的 AMPA受体数量的调控很可能是产生LTP和synaptic plasticity的主要机制。 4 1 Regulation of trafficking Biosynthesis of AMPA receptors 2 Transport along dendrites 3 Local insertion and removal from synapses
• 但是现实中Glu. R 1和Glu. R 2异源聚合成的AMPAR的电 导比同聚Glu. R 1型的低很多，虽然Ca. MKII仍然磷酸化 Glu. R 1的831位丝氨酸，其对通道电导没有影响（ Glu. R 2似乎存在对Glu. R 1的上位作用）。PKA对Glu. R 1 的845位丝氨酸磷酸化，能提高同聚Glu. R 1型AMPAR的 开放频率，其作用是否在现实的Glu. R 1/Glu. R 2异聚体也 会被Glu. R 2掩盖，有待研究。
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暑期实践口头报告会： 9月27 日，报告厅 Oral presentation ppt file Written report file 请将以上2个文件在 9月21日下午5： 00前传至：孙夏琴： 10811017@pku. edu. cn 62754880
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