Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
Laboratory of Immunoendocrinology, Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna St., 31-343 Kraków, Poland.
Neurobiol Dis. 2023 Aug;184:106219. doi: 10.1016/j.nbd.2023.106219. Epub 2023 Jul 6.
Accumulating evidence indicates that early adverse life experiences may be involved in the pathogenesis of Alzheimer's disease (AD). Prenatal stress (PS) can affect brain maturation and neuroimmune and metabolic interactions, leading to age-dependent cognitive deficits in offspring. However, a multi-faceted cause-and-effect impact of PS on the development of cognitive deficits in the process of physiological ageing and in the APP mouse model of Alzheimer's disease has not yet been evaluated. We have identified age-dependent cognitive learning and memory deficits using male C57BL/6 J (wild type, WT) and the knock-in APP (KI) aged 12, 15, and 18 months. An increase in the Aβ42/Aβ40 ratio and mouse ApoE levels in the hippocampus and frontal cortex preceded the onset of cognitive deficits in the KI mice. Moreover, dysfunction in insulin signaling, including increased IRS-1 serine phosphorylation in both brain areas and the tyrosine phosphorylation deficit in the frontal cortex, suggested age-dependent insulin/IGF-1 resistance. Resistance was reflected by disturbances in mTOR or ERK1/2 kinase phosphorylation and excessive pro-inflammatory (TNF-α, IL-6, and IL-23) status in the KI mice. Importantly, our study has provided insights into the higher vulnerability to PS-induced exacerbation of age-dependent cognitive deficits and biochemical dysfunction in KI mice than in WT animals. We anticipate our study will lead to future investigation of a multi-faceted cause-and-effect relationship between stress during neurodevelopment and the onset of AD pathology, distinguishing it from changes in the course of dementia during normal ageing.
越来越多的证据表明，早期不良生活经历可能与阿尔茨海默病（AD）的发病机制有关。产前应激（PS）会影响大脑成熟和神经免疫及代谢的相互作用，导致后代出现年龄依赖性认知缺陷。然而，PS 对生理衰老过程中和 APP 转基因 AD 小鼠模型中认知缺陷发展的多方面因果影响尚未得到评估。我们使用雄性 C57BL/6J（野生型，WT）和 APP 敲入（KI）小鼠（12、15 和 18 月龄），鉴定出了年龄依赖性认知学习和记忆缺陷。在 KI 小鼠出现认知缺陷之前，海马体和前额叶皮质中的 Aβ42/Aβ40 比值和小鼠载脂蛋白 E（ApoE）水平增加。此外，胰岛素信号转导功能障碍，包括两个脑区 IRS-1 丝氨酸磷酸化增加和前额叶皮质酪氨酸磷酸化不足，提示存在年龄依赖性胰岛素/IGF-1 抵抗。抵抗反映在 mTOR 或 ERK1/2 激酶磷酸化紊乱和 KI 小鼠中过度的促炎（TNF-α、IL-6 和 IL-23）状态。重要的是，我们的研究提供了深入的见解，即与 WT 动物相比，KI 小鼠对 PS 诱导的年龄依赖性认知缺陷和生化功能障碍的加剧更为敏感。我们预计，我们的研究将有助于未来研究神经发育期间应激与 AD 病理发生之间的多方面因果关系，将其与正常衰老过程中痴呆症病程的变化区分开来。
