Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425, Jülich, Germany.
Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich Heine University Düsseldorf, Leibniz Centre for Diabetes Research, Düsseldorf, Germany.
Mol Neurobiol. 2019 Mar;56(3):2211-2223. doi: 10.1007/s12035-018-1209-3. Epub 2018 Jul 12.
Oligomers of the amyloid-β (Aβ) protein are suspected to be responsible for the development and progression of Alzheimer's disease. Thus, the development of compounds that are able to eliminate already formed toxic Aβ oligomers is very desirable. Here, we describe the in vivo efficacy of the compound RD2, which was developed to directly and specifically eliminate toxic Aβ oligomers. In a truly therapeutic, rather than a preventive study, oral treatment with RD2 was able to reverse cognitive deficits and significantly reduce Aβ pathology in old-aged transgenic Alzheimer's Disease mice with full-blown pathology and behavioral deficits. For the first time, we demonstrate the in vivo target engagement of RD2 by showing a significant reduction of Aβ oligomers in the brains of RD2-treated mice compared to placebo-treated mice. The correlation of Aβ elimination in vivo and the reversal of cognitive deficits in old-aged transgenic mice support the hypothesis that Aβ oligomers are relevant not only for disease development and progression, but also offer a promising target for the causal treatment of Alzheimer's disease.
淀粉样蛋白-β (Aβ) 蛋白的寡聚物被怀疑是导致阿尔茨海默病发展和进展的原因。因此，开发能够消除已形成的有毒 Aβ 寡聚物的化合物是非常可取的。在这里，我们描述了化合物 RD2 的体内疗效，该化合物是专门开发用于直接消除有毒 Aβ 寡聚物的。在一项真正的治疗性而不是预防性研究中，用 RD2 进行口服治疗能够逆转认知缺陷，并显著减少具有全面病理和行为缺陷的老年转基因阿尔茨海默病小鼠的 Aβ 病理。我们首次通过显示与安慰剂治疗的小鼠相比，RD2 治疗的小鼠大脑中的 Aβ 寡聚物显著减少，证明了 RD2 的体内靶标结合。Aβ 消除与老年转基因小鼠认知缺陷逆转的相关性支持这样一种假设，即 Aβ 寡聚物不仅与疾病的发展和进展有关，而且为阿尔茨海默病的因果治疗提供了一个有希望的靶点。
