Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Institute of Gerontology, The University of Tokyo, Tokyo, Japan.
Sci Rep. 2019 Mar 11;9(1):4023. doi: 10.1038/s41598-019-40726-z.
Inflammation is a critical feature of aging and its related diseases, including cardiovascular diseases. Recent epidemiological studies demonstrated that abdominal aortic aneurysm (AAA), an aging-related vascular pathological condition, is associated with cognitive decline. However, the underlying mechanism, especially the role of vascular inflammation, is largely unknown because of lack of an available animal model. In this study, we examined whether vascular inflammation affects synaptic and cognitive dysfunction, using an AAA mouse model. In young (3 months) and middle-aged (12 months) C57BL/6J mice, AAA was induced by angiotensin II infusion with calcium chloride application. After 4 weeks of induction, aortic diameter was significantly increased and excessive Mac3-positive inflammatory cells infiltrated the destroyed aorta in middle-aged mice. AAA-induced middle-aged mice further exhibited cognitive impairment. Neuronal loss was observed in the CA3 region of the hippocampus. IBA1/MHCII-double-positive microglia activation was also seen in the hippocampus, suggesting that vascular inflammation drives neuroinflammation and subsequent cognitive dysfunction. Furthermore, we found that senescence-accelerated mice prone 8 exhibited robust AAA formation and a marked decrease of cognitive and synaptic function in the hippocampus mediated by inflammation. In conclusion, this novel murine model convincingly suggested the occurrence of vascular inflammation-derived cognitive dysfunction.
炎症是衰老及其相关疾病的一个关键特征，包括心血管疾病。最近的流行病学研究表明，腹主动脉瘤（AAA），一种与衰老相关的血管病理状况，与认知能力下降有关。然而，由于缺乏可用的动物模型，其潜在机制，特别是血管炎症的作用，在很大程度上仍是未知的。在这项研究中，我们使用 AAA 小鼠模型研究了血管炎症是否会影响突触和认知功能障碍。在年轻（3 个月）和中年（12 个月）C57BL/6J 小鼠中，通过用氯化钙应用输注血管紧张素 II 来诱导 AAA。诱导 4 周后，中年小鼠的主动脉直径显著增加，破坏的主动脉中大量 Mac3 阳性炎症细胞浸润。AAA 诱导的中年小鼠进一步表现出认知障碍。在海马体的 CA3 区观察到神经元丢失。在海马体中也观察到 IBA1/MHCII-双阳性小胶质细胞激活，表明血管炎症驱动神经炎症和随后的认知功能障碍。此外，我们发现易发生衰老加速的小鼠 8 表现出强烈的 AAA 形成，以及炎症介导的海马体认知和突触功能的明显下降。总之，这个新的小鼠模型令人信服地表明了血管炎症引起的认知功能障碍的发生。
