The Role of Soluble Oligomers of the Amyloid-beta Protein in Alzheimer’s Disease: from Synapse to Cytoskeleton.

报告题目：The Role of Soluble Oligomers of the Amyloid-beta Protein in Alzheimer’s Disease: from Synapse to Cytoskeleton.
报 告 人：Ming Jin, Ph.D.（Research Fellow in Neurology, Brigham and Women’s Hospital,Harvard Medical School）
报告时间：2011年9月30日（周五）上午9:00
报告地点：独墅湖校区二期云轩楼1319室

报告摘要：
Alzheimer’s disease is the most insidious and devastating neurodegenerative disease. It is believed to afflict 20 to 30 million people worldwide, and has been recognized as a major health problem in modern society. The significance of research on the mechanism and clinical approach of Alzheimer’s disease is not only for scientific field but also for the community. Insoluble fibrillar plaques of ) and neurofibrillary deposits of hyperphosphorylated taub -proteins (Abamyloid  proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small,  raises the keyb diffusible oligomers may be the principal bioactive form of A question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of  peptides of one defined length at supraphysiologicalb synthetic A concentrations, but the existence of such assemblies in the AD brain is not  dimers, the most abundant form of solubleb established. Here, we isolated A oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, b whereas overexpressing human tau accelerated them. Coadministering A N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.

报告人简历：

EDUCATION/TRAINING

2000   南京大学生物化学系          B.S.     生物化学

2005   中国科学院神经科学研究所    Ph.D.    神经生物学

Positions and Employment

2005-2007     Postdoctoral Fellow, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China

2008 -            Research Fellow in Neurology, Harvard Medical School

2008 -               Research Fellow, Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital

Other Experience and Professional Memberships

2005 -                Member, Society for Neuroscience

Selected peer-reviewed publications (in chronological order).

1.Yuan XB*, Jin M*, Xu XH*, Song YQ, Wu CP, Poo MM, Duan SM.  Signalling and crosstalk of Rho GTPases in mediating axon guidance.  Nat Cell Biol 2003; 5: 38-45.

2.Jin M*, Guan CB*, Jiang Y*, Chen G, Zhao CT, Cui K, Song YQ, Wu CP, Poo MM, Yuan XB.  Ca²⁺-dependent Regulation of Rho GTPases Triggers Turning of Nerve Growth Cones.  J Neurosci 2005; 25: 2338-2347.

3.Guan CB, Xu HT, Jin M, Yuan XB, Poo MM.  Long-range Ca²⁺ Signaling from Growth Cone to Soma Mediates Reversal of Neuronal Migration Induced by Slit-2. Cell 2007; 129: 385-95.

4.Chen G*, Sima J*, Jin M*, Wang KY, Xue XJ, Zheng W, Ding YQ, Yuan XB. Semaphorin-3A guides radial migration of cortical neurons during development. Nat Neurosci 2008; 11: 36-44.

5.Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe D. Soluble Amyloid beta-Protein Dimers Isolated from Alzheimer Cortex Directly Induce Tau Hyperphosphorylation and Neuritic Degeneration. Proc Natl Acad Sci U S A 2011; 108(14):5819-24. 

6.Li S*, Jin M*, Koeglsperger T, Shepardson N, Shankar G and Selkoe D. Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 2011; 31: 6627-6638.

*These authors contribute equally to this work.