Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?
Intraneuronal Aβ as a trigger for neuron loss: can this be translated into human pathology?
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DOI：
10.1042/bst0390857
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发表时间：
2011-08-01
影响因子：
3.9
通讯作者：
Wirths, Oliver
中科院分区：
文献类型：
--
作者：
Bayer, Thomas A.;Wirths, Oliver
在本综述中，我们总结了目前在转基因小鼠早期神经元内A β（淀粉样β肽）积累及其病理后果的建模方面取得的成就。特别重要的是将讨论最近的发展和结果转化为AD（阿尔茨海默病）。n端截断的A β (pE3) （A β在位置3以焦谷氨酸开始）代表了AD患者大脑中所有A β肽的主要部分。最近，我们产生了一种新的mAb（单克隆抗体）9D5，它可以选择性地识别a β (pE3)的寡聚物组装，并通过转基因小鼠模型以及来自散发性和家族性AD病例的人脑，证明了寡聚物a β (pE3)在体内的潜在参与。在散发性AD患者和非痴呆对照组中，9D5显示出不寻常的染色模式，几乎无法检测到斑块。有趣的是，在散发性和家族性AD病例中，观察到明显的神经元内染色。此外，5XFAD小鼠的9D5被动免疫显著降低了总体A β水平，稳定了行为缺陷。总之，我们已经证明，在模型系统和AD患者中，神经元内A β是一个有效的风险因素。阿尔茨海默病病理的这一特征成功地鉴定了新的低分子质量寡聚A β特异性抗体，用于诊断和治疗。
In the present review, we summarize the current achievements of modelling early intraneuronal A beta (amyloid beta-peptide) accumulation in transgenic mice with the resulting pathological consequences. Of special importance will be to discuss recent developments and the translation of the results to AD (Alzheimer's disease). N-terminally truncated A beta(pE3) (A beta starting with pyroglutamate at position 3) represents a major fraction of all A beta peptides in the brain of AD patients. Recently, we generated a novel mAb (monoclonal antibody), 9D5, that selectively recognizes oligomeric assemblies of A beta(pE3) and demonstrated the potential involvement of oligomeric A beta(pE3) in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost non-detectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal staining was observed. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall A beta levels and stabilized behavioural deficits. In summary, we have demonstrated that intraneuronal A beta is a valid risk factor in model systems and AD patients. This feature of AD pathology was successful in identifying novel low-molecular-mass oligomeric A beta-specific antibodies for diagnosis and therapy.