Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse.
Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse.
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DOI：
10.1186/1750-1326-6-20
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发表时间：
2011-03-06
影响因子：
15.1
通讯作者：
Matsubara E
中科院分区：
文献类型：
--
作者：
Takamura A;Okamoto Y;Kawarabayashi T;Yokoseki T;Shibata M;Mouri A;Nabeshima T;Sun H;Abe K;Urisu T;Yamamoto N;Shoji M;Yanagisawa K;Michikawa M;Matsubara E
几条证据表明，记忆丧失是由可溶性淀粉样蛋白β（Aβ）寡聚体引起的突触失效。然而，Aβ寡聚体（AβOs）作为突触或神经元变性的触发剂的病理相关性以及内源性AβOs神经毒性作用的可能机制仍有待确定。为了在体内特异性靶向毒性AβOs，使用新的设计方法产生了对其特异性的单克隆抗体（1A 9和2C 3）。在蓝色非变性聚丙烯酰胺凝胶电泳上，1A 9和2C 3分别特异性识别大于35聚体和五聚体的可溶性Aβ O。原子力显微镜（AFM）的生物物理和结构分析表明，神经毒性1A 9和2C 3低聚构象显示非纤维状，相对球形结构。值得注意的是，这样的Aβ 0被神经母细胞瘤（SH-SY 5 Y）细胞摄取，导致神经元死亡。在人类中，使用1A 9或2C 3的免疫组织化学分析显示，1A 9和2C 3染色的神经元内颗粒积聚在锥体神经元的核周体和一些弥漫性斑块中。FluoroJade-B结合试验也显示1A 9-或2C 3-染色的神经元，表明它们即将变性。在使用活性1A 9或2C 3抗体的长期低剂量预防性试验中，我们发现被动免疫保护阿尔茨海默病（AD）小鼠模型免受记忆缺陷、突触变性、神经元内AβOs促进和神经元变性的影响。由于1A 9和2C 3的主要抗毒性作用发生在神经元外，我们的结果表明，细胞外AβOs启动了AD毒性过程，神经元内AβOs可能加重神经元变性和记忆丧失。现在，我们有证据表明HMW-Aβ O是小鼠和人类AD毒性过程的最早表现之一。我们确信，我们的研究使我们更接近于找到治疗靶点和/或确认我们治疗策略的相关性的目标。
Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined. To specifically target toxic AβOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss. Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.
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影响因子：
15.1
作者：
Kayed R;Head E;Sarsoza F;Saing T;Cotman CW;Necula M;Margol L;Wu J;Breydo L;Thompson JL;Rasool S;Gurlo T;Butler P;Glabe CG
通讯作者：
Glabe CG
影响因子：
5.5
作者：
Mori, C;Spooner, ET;Lemere, CA
通讯作者：
Lemere, CA
DOI：
10.1073/pnas.022662599
发表时间：
2002-02-05
影响因子：
11.1
作者：
O'Nuallain, B;Wetzel, R
通讯作者：
Wetzel, R
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH
影响因子：
4.7
作者：
Lambert, MP;Viola, KL;Klein, WL
通讯作者：
Klein, WL