Ushakova Valeriya, Zorkina Yana, Abramova Olga, Kuanaeva Regina, Barykin Evgeny, Vaneev Alexander, Timoshenko Roman, Gorelkin Peter, Erofeev Alexander, Zubkov Eugene, Valikhov Marat, Gurina Olga, Mitkevich Vladimir, Chekhonin Vladimir, Morozova Anna
Department of Basic and Applied Neurobiology, V.P. Serbsky National Medical Research Center of Psychiatry and Narcology, The Ministry of Health of the Russian Federation, 119034 Moscow, Russia.
Department of Higher Nervous Function, Lomonosov Moscow State University, 119991 Moscow, Russia.
Brain Sci. 2024 Oct 21;14(10):1042. doi: 10.3390/brainsci14101042.
BACKGROUND/OBJECTIVES: One of the hallmarks of Alzheimer's disease (AD) is the accumulation of aggregated beta-amyloid (Aβ) protein in the form of senile plaques within brain tissue. Senile plaques contain various post-translational modifications of Aβ, including prevalent isomerization of Asp7 residue. The Asp7 isomer has been shown to exhibit increased neurotoxicity and induce amyloidogenesis in brain tissue of transgenic mice. The toxicity of Aβ peptides may be partly mediated by their structure and morphology. In this respect, in this study we analyzed the structural and aggregation characteristics of the Asp7 isoform of Aβ and compared them to those of synthetic Aβ. We also investigated the effects of intracerebroventricular (i.c.v.) administration of these peptides, a method often used to induce AD-like symptoms in rodent models.
Atomic force microscopy (AFM) was conducted to compare the morphological and aggregation properties of Aβ and Asp7 iso-Aβ. The effects of i.c.v. stereotaxic administration of the proteins were assessed via behavioral analysis and reactive oxygen species (ROS) estimation in vivo using a scanning ion-conductance microscope with a confocal module.
AFM measurements revealed structural differences between the two peptides, most notably in their soluble toxic oligomeric forms. The i.c.v. administration of Asp7 iso-Aβ induced spatial memory deficits in rats and elevated oxidative stress levels in vivo, suggesting a potential of ROS in the pathogenic mechanism of the peptide.
The findings support the further investigation of Asp7 iso-Aβ in translational research on AD and suggest its involvement in neurodegenerative processes.
背景/目的：阿尔茨海默病（AD）的标志性特征之一是脑组织中以老年斑形式存在的聚集β-淀粉样蛋白（Aβ）的积累。老年斑含有Aβ的各种翻译后修饰，包括Asp7残基普遍的异构化。已表明Asp7异构体表现出增强的神经毒性，并在转基因小鼠的脑组织中诱导淀粉样蛋白生成。Aβ肽的毒性可能部分由其结构和形态介导。在这方面，在本研究中，我们分析了Aβ的Asp7异构体的结构和聚集特性，并将它们与合成Aβ的特性进行了比较。我们还研究了脑室内（i.c.v.）注射这些肽的效果，这是一种常用于在啮齿动物模型中诱导AD样症状的方法。
进行原子力显微镜（AFM）以比较Aβ和Asp7异构体Aβ的形态和聚集特性。通过行为分析和使用带有共聚焦模块的扫描离子传导显微镜在体内估计活性氧（ROS）来评估蛋白质i.c.v.立体定向给药的效果。
AFM测量揭示了两种肽之间的结构差异，最明显的是它们的可溶性毒性寡聚体形式。i.c.v.注射Asp7异构体Aβ会导致大鼠空间记忆缺陷并提高体内氧化应激水平，表明ROS在该肽的致病机制中具有潜在作用。
这些发现支持在AD的转化研究中进一步研究Asp7异构体Aβ，并表明其参与神经退行性过程。
