The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade.
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade.
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DOI：
10.3233/jad-179941
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Klein WL
中科院分区：
文献类型：
--
作者：
Cline EN;Bicca MA;Viola KL;Klein WL
淀粉样蛋白-β寡聚体（AβO）假说于1998年提出。研究表明，可溶性配体样AβOs是导致阿尔茨海默病（AD）的脑损伤的主要因素。这一假设基于以下发现：AβOs的无原纤维合成制剂是有效的CNS神经毒素，其迅速抑制长时程增强，并随着时间的推移导致选择性神经细胞死亡（Lambert et al.，1998年）。该机制归因于由未知毒素受体介导的涉及酪氨酸蛋白激酶Fyn的破坏的信号传导。自那时以来，已经发表了4,000多篇关于AβOs的文章，其中包括400多篇综述。已显示Aβ 0在人类和动物模型脑组织中以AD依赖性方式积累，并且在实验上损害学习和记忆并引发AD神经病理学的主要方面，包括tau病理学、突触退化和丧失、炎症和氧化损伤。正如Hayden和Teplow在2013年所回顾的那样，AβO假说“几乎取代了淀粉样蛋白级联反应”。尽管对AβOs在AD发病机制中所起作用的认识不断加深，但AβOs尚未受到对淀粉样斑块的临床关注，淀粉样斑块一直是治疗和诊断的主要尝试的核心，但不再被视为Aβ的最致病形式。然而，如果AβO研究的势头继续下去，特别是努力阐明结构的关键方面，可以设想一条成功的疾病修饰治疗的清晰途径。确保从最近的晚期临床失败中吸取的经验教训在整个治疗开发过程中得到适当应用，将进一步提高近期成功治疗的可能性。
The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer’s disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis “has all but supplanted the amyloid cascade.” Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.