Division of Psychiatry Research, University of Zurich, Zurich, Switzerland.
PLoS One. 2011 Apr 5;6(4):e18296. doi: 10.1371/journal.pone.0018296.
Amyloid-beta peptide (Aβ)-directed active and passive immunization therapeutic strategies reduce brain levels of Aβ, decrease the severity of beta-amyloid plaque pathology and reverse cognitive deficits in mouse models of Alzheimer's disease (AD). As an alternative approach to passive immunization with full IgG molecules, single-chain variable fragment (scFv) antibodies can modulate or neutralize Aβ-related neurotoxicity and inhibit its aggregation in vitro. In this study, we characterized a scFv derived from a full IgG antibody raised against the C-terminus of Aβ, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aβ-related pathology. We found that the scFv entered the brain after intranasal application, and that it bound to beta-amyloid plaques in the cortex and hippocampus of APP transgenic mice. Moreover, the scFv inhibited Aβ fibril formation and Aβ-mediated neurotoxicity in vitro. In a preventative therapeutic approach chronic intranasal treatment with scFv reduced congophilic amyloid angiopathy (CAA) and beta-amyloid plaque numbers in the cortex of APPswe/PS1dE9 mice. This reduction of CAA and plaque pathology was associated with a redistribution of brain Aβ from the insoluble fraction to the soluble peptide pool. Due to their lack of the effector domain of full IgG, scFv may represent an alternative tool for the treatment of Aβ-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aβ-directed immunotherapy can reduce Aβ deposition in brain vessels in transgenic mice.
淀粉样β肽（Aβ）靶向主动和被动免疫治疗策略可降低大脑中的 Aβ 水平，减轻β-淀粉样斑块病理学的严重程度，并逆转阿尔茨海默病（AD）小鼠模型中的认知缺陷。作为被动免疫全 IgG 分子的替代方法，单链可变片段（scFv）抗体可以调节或中和与 Aβ 相关的神经毒性，并抑制其在体外聚集。在这项研究中，我们对一种源自针对 Aβ C 末端的全 IgG 抗体的 scFv 进行了表征，并研究了其进入 APP 转基因小鼠大脑的情况，以及其降低与 Aβ 相关的病理学的潜力。我们发现，scFv 经鼻内应用后进入大脑，并与 APP 转基因小鼠大脑皮质和海马体中的β-淀粉样斑块结合。此外，scFv 在体外抑制 Aβ 纤维形成和 Aβ 介导的神经毒性。在预防性治疗方法中，慢性鼻内给予 scFv 可减少 APPswe/PS1dE9 小鼠大脑皮质中的嗜刚果红血管病（CAA）和β-淀粉样斑块数量。CAA 和斑块病理学的减少与大脑 Aβ 从不溶性部分重新分布到可溶性肽池中有关。由于缺乏全 IgG 的效应结构域，scFv 可能代表一种替代工具，用于治疗与 Aβ 相关的病理学，而不会引发 Fc 介导的效应功能。此外，我们的观察结果支持这样一种可能性，即 Aβ 靶向免疫疗法可以减少转基因小鼠大脑血管中的 Aβ 沉积。
