Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.
East Tallinn Central Hospital Eye Clinic, Tallinn, Estonia.
J Alzheimers Dis. 2022;85(2):715-728. doi: 10.3233/JAD-215026.
Alzheimer's disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-β (Aβ) peptides. Besides major amyloid-targeting approach there is the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess of extracellular copper.
In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and search for new copper-regulating ligands.
We used cell culture, ICP MS, and Drosophila melanogaster models of AD.
We demonstrate that the natural intracellular copper chelator, α-lipoic acid (LA) translocates copper from extracellular to intracellular space in an SH-SY5Y-based neuronal cell model and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster models of AD from developing AD phenotype by improving locomotor activity of fruit fly with overexpression of human Aβ with Iowa mutation in the fly brain. In addition, LA slightly weakens copper-induced smooth eye phenotype when amyloid-β protein precursor (AβPP) and beta-site AβPP cleaving enzyme 1 (BACE1) are overexpressed in eye photoreceptor cells.
Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD.
阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，也是痴呆症的最常见病因。AD 的治疗和预防存在巨大的未满足需求。AD 的一个标志是大脑中细胞外淀粉样斑块的形成，由淀粉样β（Aβ）肽组成。除了主要的淀粉样靶向方法外，还需要关注替代治疗策略。AD 发病的一个因素是铜代谢失调，表现为细胞内铜缺乏和细胞外铜过剩。
在目前的研究中，我们遵循广泛接受的假说，即铜代谢的正常化可导致疾病的预防或减缓，并寻找新的铜调节配体。
我们使用细胞培养、ICP-MS 和 AD 的黑腹果蝇模型。
我们证明，天然细胞内铜螯合剂α-硫辛酸（LA）将铜从细胞外转运到基于 SH-SY5Y 的神经元细胞模型的细胞内空间，因此适合缓解 AD 神经元特征性的细胞内铜缺乏。此外，我们表明，LA 的补充通过改善具有在果蝇大脑中表达人 Aβ 的 Iowa 突变的果蝇的运动活动，保护 AD 的黑腹果蝇模型免于发展出 AD 表型。此外，当在眼感光细胞中过度表达淀粉样前体蛋白（AβPP）和β-位点 AβPP 切割酶 1（BACE1）时，LA 略微减弱了铜诱导的平滑眼表型。
总之，这些结果提供了证据表明 LA 具有使 AD 中的铜代谢正常化的潜力。
