Sapkota Arjun, Halder Sebok K, Milner Richard
San Diego Biomedical Research Institute, San Diego, CA 92121, USA.
Brain Commun. 2024 Dec 17;7(1):fcae456. doi: 10.1093/braincomms/fcae456. eCollection 2025.
Hypoxia triggers blood-brain barrier disruption and a strong microglial activation response around leaky cerebral blood vessels. These events are greatly amplified in aged mice which is translationally relevant because aged patients are far more likely to suffer hypoxic events from heart or lung disease, and because of the pathogenic role of blood-brain barrier breakdown in vascular dementia. Importantly, it is currently unclear if disrupted cerebral blood vessels spontaneously repair and if they do, whether surrounding microglia deactivates. In this study, we addressed these questions by exposing aged (20 months old) mice to chronic mild hypoxia (8% O) for 7 days and then returned them to normoxic conditions for 7 or 14 days, before evaluating blood-brain barrier disruption and microglial activation at the different timepoints. Seven days chronic mild hypoxia triggered marked blood-brain barrier disruption, as measured by extravascular leak of fibrinogen and red blood cells, which led to enhanced microglial activation, as measured by Mac-1 and CD68 levels. Interestingly, while return to normoxia promoted spontaneous repair of damaged blood vessels, the surrounding microglia remained persistently activated and were slow to deactivate. Chronic mild hypoxia also triggered neuronal loss that resulted in irreversible cognitive decline as measured by the novel object recognition test. Taken together, these findings describe an important disconnect between vascular repair and microglial deactivation in aged mice, which likely contributes to prolonged neuroinflammation. As hypoxia occurs in many age-related conditions, our data have important implications for the pathogenic role of hypoxia in the induction and progression of vascular dementia.
缺氧会引发血脑屏障破坏，并在渗漏的脑血管周围引发强烈的小胶质细胞激活反应。这些事件在老年小鼠中会被极大地放大，这在转化医学上具有相关性，因为老年患者因心脏病或肺病更易发生缺氧事件，且血脑屏障破坏在血管性痴呆中具有致病作用。重要的是，目前尚不清楚受损的脑血管是否会自发修复，如果会修复，周围的小胶质细胞是否会失活。在本研究中，我们通过将老年（20个月大）小鼠暴露于慢性轻度缺氧（8%氧气）环境7天，然后将它们恢复到常氧环境7天或14天，在不同时间点评估血脑屏障破坏和小胶质细胞激活情况，从而解决了这些问题。七天的慢性轻度缺氧引发了明显的血脑屏障破坏，通过纤维蛋白原和红细胞的血管外渗漏来衡量，这导致了小胶质细胞激活增强，通过Mac-1和CD68水平来衡量。有趣的是，虽然恢复到常氧促进了受损血管的自发修复，但周围的小胶质细胞仍持续激活且失活缓慢。慢性轻度缺氧还引发了神经元损失，通过新物体识别测试衡量，导致了不可逆的认知衰退。综上所述，这些发现描述了老年小鼠血管修复和小胶质细胞失活之间的重要脱节，这可能导致神经炎症延长。由于缺氧发生在许多与年龄相关的疾病中，我们的数据对于缺氧在血管性痴呆的诱导和进展中的致病作用具有重要意义。
