抗α-突触核蛋白寡聚物/原原纤维单克隆抗体治疗转基因小鼠脑干病理减少和早期认知症状的短暂改善

IF 1.7 Q3 CLINICAL NEUROLOGY Aging brain Pub Date : 2023-01-01 DOI:10.1016/j.nbas.2023.100086
S. Ekmark-Lewén , A. Aniszewska , A. Molisak , A. Gumucio , V. Lindström , P.J. Kahle , E. Nordström , C. Möller , J. Fälting , L. Lannfelt , J. Bergström , M. Ingelsson
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引用次数: 0

摘要

针对α-突触核蛋白(α-syn)的免疫治疗是治疗帕金森病(PD)和相关α-突触蛋白疾病的一种很有前途的新策略。我们之前已经表明,用靶向细胞毒性α-syn的单克隆寡聚物/原纤维选择性抗体mAb47进行全身治疗会导致这些物种的中枢神经系统水平降低,并表明衰老(Thy-1)-h[A30P]α-syn转基因小鼠的晚期症状降低。在这里,我们用这种抗体进行了一项早发性长期治疗研究,以评估在同一小鼠模型中对大脑病理和行为结果的影响。与安慰剂组相比,该治疗显著降低了上脑干的磷酸化α-syn(pS129α-syn)病理。此外,在6个月大的抗体治疗小鼠中可以看到保留的识别记忆和风险评估行为,尽管这些影响在11个月大时不再显著。重要的是,该治疗没有发现炎症反应或其他潜在毒性作用的证据。总之,这项研究支持用单克隆抗体靶向α-突触低聚物/原纤维的策略,以对抗早期症状并减缓PD和其他α-突触核蛋白疾病的进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Reduction of brain stem pathology and transient amelioration of early cognitive symptoms in transgenic mice treated with a monoclonal antibody against α-synuclein oligomers/protofibrils

Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] α-syn transgenic mice.

Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated α-syn (pS129 α-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target α-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other α-synucleinopathies.

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Aging brain
Aging brain Neuroscience (General), Geriatrics and Gerontology
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