Abstract：
Alzheimer\'s disease (AD) is a multifactorial neurodegenerative disease with a complex origin, thought to involve a combination of genetic, biological and environmental factors. Insulin dysfunction has emerged as a potential factor contributing to AD pathogenesis, particularly in individuals with diabetes, and among those with insulin deficiency or undergoing insulin therapy. The intraperitoneal administration of streptozotocin (STZ) is widely used in rodent models to explore the impact of insulin deficiency on AD pathology, although prior research predominantly focused on young animals, with no comparative analysis across different age groups. Our study aimed to fill this gap by analyzing the impact of insulin dysfunction in 7 and 23 months 3xTg-AD mice, that exhibit both amyloid and tau pathologies. Our objective was to elucidate the age-specific consequences of insulin deficiency on AD pathology. STZ administration led to insulin deficiency in the younger mice, resulting in an increase in cortical amyloid-β (Aβ) and tau aggregation, while tau phosphorylation was not significantly affected. Conversely, older mice displayed an unexpected resilience to the peripheral metabolic impact of STZ, while exhibiting an increase in both tau phosphorylation and aggregation without significantly affecting amyloid pathology. These changes were paralleled with alterations in signaling pathways involving tau kinases and phosphatases. Several markers of blood-brain barrier (BBB) integrity declined with age in 3xTg-AD mice, which might have facilitated a direct neurotoxic effect of STZ in older mice. Overall, our research confirms the influence of insulin signaling dysfunction on AD pathology, but also advises careful interpretation of data related to STZ-induced effects in older animals.
摘要：
阿尔茨海默病(AD)是一种起源复杂的多因素神经退行性疾病,被认为涉及遗传的组合，生物和环境因素。胰岛素功能障碍已成为导致AD发病的潜在因素。特别是糖尿病患者，以及胰岛素缺乏或接受胰岛素治疗的患者。链脲佐菌素（STZ）的腹腔内给药是一种广泛使用的啮齿动物模型，用于探索胰岛素缺乏对AD病理的影响，尽管之前的研究主要集中在幼小动物身上，没有不同年龄段的比较分析。我们的研究旨在通过分析7个月和23个月3xTg-AD小鼠的胰岛素功能障碍的影响来填补这一空白，表现出淀粉样蛋白和tau病理。我们的目的是阐明胰岛素缺乏对AD病理的年龄特异性后果。STZ给药导致年轻小鼠的胰岛素缺乏，导致皮质淀粉样蛋白β（Aβ）和tau聚集增加，而tau磷酸化没有显著影响。相反，年龄较大的小鼠对STZ的外周代谢影响表现出意想不到的复原力，同时表现出tau磷酸化和聚集的增加，而不会显着影响淀粉样蛋白病理。这些变化与涉及tau激酶和磷酸酶的信号传导途径的改变平行。在3xTg-AD小鼠中，血脑屏障（BBB）完整性的几种标志物随年龄而下降，这可能促进STZ对老年小鼠的直接神经毒性作用。总的来说,我们的研究证实了胰岛素信号传导功能障碍对AD病理的影响，但也建议仔细解释与STZ在老年动物中引起的影响有关的数据。
