Youssef Yomna A, Tammam Salma N, Elshenawy Basma M, Ilyas Shaista, Gad Alaa A, Farag Karin S, Mathur Sanjay, Abdel-Kader Reham M
Department of Pharmaceutical Technology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt.
Institute of Inorganic Chemistry, University of Cologne, Greinstraβe 6, 50939 Cologne, Germany.
Eur J Pharm Biopharm. 2025 Sep;214:114778. doi: 10.1016/j.ejpb.2025.114778. Epub 2025 Jun 6.
Alzheimer's disease (AD) is the most prevalent form of dementia. Mitochondrial dysfunction is recognized among the earliest pathological events in AD, and is closely-linked with the accumulation of amyloid-beta (Aβ) plaques which is a well-established hallmark of AD. The interplay between the two converges on the interaction of Aβ with the mitochondrial enzyme Aβ-binding alcohol dehydrogenase (ABAD), and the formation of Aβ-ABAD complex. This leads to the suppression of the normal function of ABAD, and elicits a number of detrimental events such as the excessive generation of reactive oxygen species (ROS) resulting in apoptosis of neuronal cells. To intercept the Aβ-ABAD interaction, a decoy peptide (DP) was employed, and was loaded into polymeric chitosan nanoparticles (CSNPs) for efficient delivery across the blood-brain barrier (BBB). In vivo studies on control and neuroinflammatory mouse models confirmed that NPs of the smaller size (SNPs; 59 ± 6 nm) accumulated in the brain with minimal off-target delivery. Unlike free DP, DP-loaded SNPs significantly improved cognitive functions as depicted by the modified Y-maze test. The DP also had protective effects on the mitochondria that were associated with a decrease in Aβ, an increase in ATP and a normalization in SOD activity. Additionally, the restoration of ABAD normal function was reflected by elevated estradiol levels. These findings indicate that the inhibition of Aβ-ABAD complex ameliorates Aβ-induced toxicity in AD, consequently enhancing both mitochondrial and cognitive functions.
阿尔茨海默病（AD）是最常见的痴呆形式。线粒体功能障碍是AD最早出现的病理事件之一，并且与淀粉样β蛋白（Aβ）斑块的积累密切相关，而Aβ斑块是AD公认的标志。两者之间的相互作用集中在Aβ与线粒体酶Aβ结合乙醇脱氢酶（ABAD）的相互作用以及Aβ-ABAD复合物的形成上。这导致ABAD的正常功能受到抑制，并引发许多有害事件，如活性氧（ROS）过度产生，导致神经元细胞凋亡。为了阻断Aβ-ABAD的相互作用，使用了一种诱饵肽（DP），并将其载入聚壳聚糖纳米颗粒（CSNP）中，以便有效地穿过血脑屏障（BBB）。对对照和神经炎症小鼠模型的体内研究证实，较小尺寸的纳米颗粒（SNP；59±6nm）在大脑中积累，脱靶递送最少。与游离DP不同，载有DP的SNP通过改良Y迷宫试验显示出显著改善认知功能。DP对线粒体也有保护作用，这与Aβ减少、ATP增加和超氧化物歧化酶（SOD）活性正常化有关。此外，雌二醇水平升高反映了ABAD正常功能的恢复。这些发现表明，抑制Aβ-ABAD复合物可改善AD中Aβ诱导的毒性，从而增强线粒体和认知功能。
