An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging.
An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging.
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DOI：
10.1038/s41598-018-22979-2
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发表时间：
2018-03-15
影响因子：
4.6
通讯作者：
Bacskai BJ
中科院分区：
文献类型：
--
作者：
Wang X;Kastanenka KV;Arbel-Ornath M;Commins C;Kuzuya A;Lariviere AJ;Krafft GA;Hefti F;Jerecic J;Bacskai BJ
可溶性β淀粉样蛋白寡聚物（a β o）是公认的神经毒素，可触发特定神经元亚群的异常信号，导致阿尔茨海默病（AD）中累积的神经元损伤和记忆障碍。a β o触发事件的一个深远的下游后果是胞质钙浓度（[Ca2+]i）的失调，这与突触失败、细胞骨架异常和最终的神经元死亡有关。我们已经开发了一种体外/体内药物筛选试验，通过测量a β o诱导的[Ca2+]i的实时变化来评估推定的a β o阻断候选药物。我们的筛选实验表明，抗a β o单克隆抗体ACU3B3对大范围的a β o具有有效的阻断能力。我们发现，微摩尔浓度的a β o能够增加原代神经元培养物中的[Ca2+]i，这一效应被ACU3B3所阻止。在暴露的皮质表面局部应用5 nM a - β o也会引起体内钙水平的显著升高，而用1 ng/mL (6.67 pM) ACU3B3预处理大脑可以完全消除钙水平的升高。我们的研究结果有力地支持了这种功能性筛选试验在识别和确认a β o阻断候选药物（如ACU3B3的人类同源物）的有效性方面的实用性，这可能成为首个验证淀粉样蛋白低聚物假说的实验性AD治疗药物。
Soluble amyloid β oligomers (AβOs) are widely recognized neurotoxins that trigger aberrant signaling in specific subsets of neurons, leading to accumulated neuronal damage and memory disorders in Alzheimer’s disease (AD). One of the profound downstream consequences of AβO-triggered events is dysregulation of cytosolic calcium concentration ([Ca2+]i), which has been implicated in synaptic failure, cytoskeletal abnormalities, and eventually neuronal death. We have developed an in vitro/in vivo drug screening assay to evaluate putative AβO-blocking candidates by measuring AβO-induced real-time changes in [Ca2+]i. Our screening assay demonstrated that the anti-AβO monoclonal antibody ACU3B3 exhibits potent blocking capability against a broad size range of AβOs. We showed that picomolar concentrations of AβOs were capable of increasing [Ca2+]i in primary neuronal cultures, an effect prevented by ACU3B3. Topical application of 5 nM AβOs onto exposed cortical surfaces also elicited significant calcium elevations in vivo, which was completely abolished by pre-treatment of the brain with 1 ng/mL (6.67 pM) ACU3B3. Our results provide strong support for the utility of this functional screening assay in identifying and confirming the efficacy of AβO-blocking drug candidates such as the human homolog of ACU3B3, which may emerge as the first experimental AD therapeutic to validate the amyloid oligomer hypothesis.
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影响因子：
16.6
作者：
Freir, Darragh B.;Nicoll, Andrew J.;Klyubin, Igor;Panico, Silvia;Mc Donald, Jessica M.;Risse, Emmanuel;Asante, Emmanuel A.;Farrow, Mark A.;Sessions, Richard B.;Saibil, Helen R.;Clarke, Anthony R.;Rowan, Michael J.;Walsh, Dominic M.;Collinge, John
通讯作者：
Collinge, John
针对适当的淀粉样β神经元毒素：阿尔茨海默病免疫治疗的前进之路。
DOI：
10.1186/alzrt272
发表时间：
2014
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Goure WF;Krafft GA;Jerecic J;Hefti F
通讯作者：
Hefti F
影响因子：
4.8
作者：
Danzer, Karin M.;Ruf, Wolfgang P.;McLean, Pamela J.
通讯作者：
McLean, Pamela J.
影响因子：
3.3
作者：
Gan KJ;Silverman MA
通讯作者：
Silverman MA
DOI：
10.1523/jneurosci.4367-12.2013
发表时间：
2013-02-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Demuro A;Parker I
通讯作者：
Parker I