Laboratory for Neurodegenerative Research, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Hale Building for Transformative Medicine, 60 Fenwood Road, Boston, MA, 02115, USA.
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Acta Neuropathol Commun. 2023 Mar 10;11(1):39. doi: 10.1186/s40478-023-01511-2.
Despite ongoing debate, the amyloid β-protein (Aβ) remains the prime therapeutic target for the treatment of Alzheimer's disease (AD). However, rational drug design has been hampered by a lack of knowledge about neuroactive Aβ. To help address this deficit, we developed live-cell imaging of iPSC-derived human neurons (iNs) to study the effects of the most disease relevant form of Aβ-oligomeric assemblies (oAβ) extracted from AD brain. Of ten brains studied, extracts from nine caused neuritotoxicity, and in eight cases this was abrogated by Aβ immunodepletion. Here we show that activity in this bioassay agrees relatively well with disruption of hippocampal long-term potentiation, a correlate of learning and memory, and that measurement of neurotoxic oAβ can be obscured by more abundant non-toxic forms of Aβ. These findings indicate that the development of novel Aβ targeting therapeutics may benefit from unbiased activity-based discovery. To test this principle, we directly compared 5 clinical antibodies (aducanumab, bapineuzumab, BAN2401, gantenerumab, and SAR228810) together with an in-house aggregate-preferring antibody (1C22) and established relative ECs in protecting human neurons from human Aβ. The results yielded objective numerical data on the potency of each antibody in neutralizing human oAβ neuritotoxicity. Their relative efficacies in this morphological assay were paralleled by their functional ability to rescue oAβ-induced inhibition of hippocampal synaptic plasticity. This novel paradigm provides an unbiased, all-human system for selecting candidate antibodies for advancement to human immunotherapy.
尽管存在持续的争论，但淀粉样β-蛋白（Aβ）仍然是治疗阿尔茨海默病（AD）的主要治疗靶点。然而，由于缺乏对神经活性 Aβ 的了解，合理的药物设计一直受到阻碍。为了帮助解决这一不足，我们开发了人诱导多能干细胞（iPSC）衍生的神经元（iNs）的活细胞成像，以研究从 AD 大脑中提取的最相关的疾病形式的 Aβ-寡聚体（oAβ）的影响。在研究的十个大脑中，有九个大脑的提取物导致神经毒性，而在八种情况下，Aβ 免疫耗竭可以消除这种毒性。在这里，我们发现该生物测定的活性与海马体长期增强的破坏相对吻合，海马体长期增强是学习和记忆的相关物，并且神经毒性 oAβ 的测量可能会被更丰富的非毒性 Aβ 形式所掩盖。这些发现表明，新型 Aβ 靶向治疗药物的开发可能会从基于活性的无偏见发现中受益。为了验证这一原理，我们直接比较了 5 种临床抗体（aducanumab、bapineuzumab、BAN2401、gantenerumab 和 SAR228810）以及一种内部的聚集优先抗体（1C22），并确定了它们在保护人类神经元免受人类 Aβ 侵害方面的相对 ECs。这些结果为每种抗体中和人类 oAβ 神经毒性的效力提供了客观的数值数据。在这种形态测定中，它们的相对功效与它们在挽救 oAβ 诱导的海马体突触可塑性抑制方面的功能能力相平行。这种新的范例为选择候选抗体进行人类免疫治疗提供了一个无偏见的、全人类的系统。
