I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, 44 Thorez av, Saint Petersburg, 194223, Russia.
School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
J Mol Neurosci. 2022 Jul;72(7):1516-1526. doi: 10.1007/s12031-022-01986-z. Epub 2022 Mar 28.
Development of the olfactory system begins early in embryogenesis and is important for the survival of new-borns in postnatal life. Olfactory malfunction in early life disrupts development of behavioural patterns while with ageing manifests development of neurodegenerative disorders. Previously, we have shown that prenatal hypoxia in rats leads to impaired olfaction in the offspring and correlates with reduced expression of a neuropeptidase neprilysin (NEP) in the brain structures involved in processing of the olfactory stimuli. Prenatal hypoxia also resulted in an increased activity of caspases in rat brain and its inhibition restored NEP content in the brain tissue and improved rat memory. In this study, we have analysed effects of intraventricular administration of a caspase inhibitor Ac-DEVD-CHO on NEP mRNA expression, the number of dendritic spines and olfactory function of rats subjected to prenatal hypoxia on E14. The data obtained demonstrated that a single injection of the inhibitor on P20 restored NEP mRNA levels and number of dendritic spines in the entorhinal and parietal cortices, hippocampus and rescued rat olfactory function in food search and odour preference tests. The data obtained suggest that caspase activation caused by prenatal hypoxia contributes to the olfactory dysfunction in developing animals and that caspase inhibition restores the olfactory deficit via upregulating NEP expression and neuronal networking. Because NEP is a major amyloid-degrading enzyme, any decrease in its expression and activity not only impairs brain functions but also predisposes to accumulation of the amyloid-β peptide and development of neurodegeneration characteristic of Alzheimer's disease.
嗅觉系统的发育始于胚胎发生早期，对于新生动物在产后生活中的生存至关重要。生命早期的嗅觉功能障碍会破坏行为模式的发展，而随着年龄的增长则会表现出神经退行性疾病的发展。以前，我们已经表明，大鼠产前缺氧会导致后代嗅觉受损，并且与参与嗅觉刺激处理的大脑结构中神经肽酶 Neprilysin（NEP）的表达减少相关。产前缺氧还导致大鼠大脑中 Caspase 的活性增加，其抑制剂的抑制作用恢复了脑组织中的 NEP 含量，并改善了大鼠的记忆。在这项研究中，我们分析了脑室给予 Caspase 抑制剂 Ac-DEVD-CHO 对 E14 时产前缺氧大鼠的 NEP mRNA 表达、树突棘数量和嗅觉功能的影响。获得的数据表明，在 P20 时单次注射抑制剂可恢复内嗅皮层和顶叶皮层、海马体中 NEP mRNA 水平和树突棘数量，并挽救大鼠在食物搜索和气味偏好测试中的嗅觉功能。获得的数据表明，产前缺氧引起的 Caspase 激活导致发育中动物的嗅觉功能障碍，而 Caspase 抑制通过上调 NEP 表达和神经元网络来恢复嗅觉缺陷。因为 NEP 是主要的淀粉样蛋白降解酶，其表达和活性的任何降低不仅会损害大脑功能，还会导致淀粉样蛋白-β肽的积累和阿尔茨海默病特征的神经退行性变。
