Jana Metta K, Cappai Roberto, Pham Chi L L, Ciccotosto Giuseppe D
Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Vic., Australia.
J Neurochem. 2016 Feb;136(3):594-608. doi: 10.1111/jnc.13443.
Amyloid beta (Aβ) peptide is the major constituent of the extracellular amyloid plaques deposited in the brains of Alzheimer's disease patients and is central to the pathogenic pathway causing this disease. The identity of the neurotoxic Aβ species remains elusive. We previously reported that Aβ toxicity correlates strongly with its neuronal cell binding leading us to hypothesize that neuronal cell death is caused by the binding of a specific oligomeric Aβ species. To identify the specific oligomeric Aβ species that is associated with cell death, we treated mouse cortical neuronal cultures with synthetic Aβ40 and Aβ42 peptides and identified that the cellular Aβ binding and neurotoxicity were time and concentration dependent. We found a significant correlation between the amount of trimer and tetramer species bound to neurons with increasing neurotoxicity. We prepared Aβ40 oligomers (up to tetramers) using photo-induced cross-linking of unmodified peptides to confirm this oligomer-specific neurotoxic activity. Our results identify the Aβ tetramer, followed by the trimer, as the most toxic low-order oligomers Aβ species. Our findings suggested that binding of amyloid-β (Aβ) tetramer and trimer, not monomer or dimer, to neurons is critical to induce neuronal cell death associated with Alzheimer's Disease. We proposed that Aβ trimer and tetramer are the potential neurotoxic Aβ species. This would provide more specific therapeutic target for Alzheimer's Disease.
淀粉样β蛋白（Aβ）肽是阿尔茨海默病患者大脑中沉积的细胞外淀粉样斑块的主要成分，并且是导致该疾病的致病途径的核心。具有神经毒性的Aβ种类仍然难以确定。我们之前报道过，Aβ毒性与其与神经元细胞的结合密切相关，这使我们推测神经元细胞死亡是由特定的寡聚Aβ种类的结合所导致的。为了鉴定与细胞死亡相关的特定寡聚Aβ种类，我们用合成的Aβ40和Aβ42肽处理小鼠皮质神经元培养物，并确定细胞Aβ结合和神经毒性具有时间和浓度依赖性。我们发现与神经元结合的三聚体和四聚体种类的数量与神经毒性增加之间存在显著相关性。我们使用未修饰肽的光诱导交联制备了Aβ40寡聚体（直至四聚体），以证实这种寡聚体特异性神经毒性活性。我们的结果确定Aβ四聚体，其次是三聚体，是毒性最强的低阶寡聚Aβ种类。我们的研究结果表明，淀粉样β蛋白（Aβ）四聚体和三聚体而非单体或二聚体与神经元的结合对于诱导与阿尔茨海默病相关的神经元细胞死亡至关重要。我们提出Aβ三聚体和四聚体是潜在的具有神经毒性的Aβ种类。这将为阿尔茨海默病提供更具体的治疗靶点。
