Departments of Neuroscience and Regenerative Medicine, and.
Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
J Neurosci. 2019 May 22;39(21):4179-4192. doi: 10.1523/JNEUROSCI.2506-18.2019. Epub 2019 Mar 18.
Obesity and insulin resistance elicit blood-brain barrier (BBB) breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood. These studies initially addressed the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. Obesity increased BBB permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), whereas diet-induced insulin resistance increased permeability to both NaFl and Evans blue, which forms a high molecular weight complex with serum albumin. Serial section transmission electron microscopy analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. Chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and we observed that acute Adora2a antagonism normalized BBB permeability in wild-type mice with diet-induced insulin resistance. Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against BBB breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against BBB breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory. These findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the BBB in dietary obesity, and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance. The blood-brain barrier (BBB) restricts the entry of circulating factors into the brain, but obesity promotes BBB breakdown in humans and animal models. We used transgenic mice with resistance to BBB breakdown to investigate the role of neurovascular dysfunction in high-fat diet (HFD)-induced cognitive impairment. Transgenic mice with inducible ablation of Adora2a in endothelial cells were protected against BBB breakdown on HFD, despite comparable metabolic impairments relative to normal mice. Transgenic mice were also resistant to HFD-induced cognitive dysfunction and were protected against deficits in hippocampal synaptic plasticity. These findings indicate that Adora2a-mediated signaling in endothelial cells mediates obesity-induced BBB breakdown, and implicate cerebrovascular dysfunction as the mechanism for deficits in synaptic plasticity and cognition with obesity and diabetes.
肥胖和胰岛素抵抗会引起人体和动物模型的血脑屏障（BBB）破坏，但这两种病理的相对贡献仍不清楚。这些研究最初旨在探讨脑血管功能障碍与雄性小鼠饮食性肥胖或饮食诱导的胰岛素抵抗之间的时间进展关系。肥胖会增加低分子量荧光染料荧光素钠（NaFl）通过 BBB 的通透性，而饮食诱导的胰岛素抵抗会增加 NaFl 和 Evans 蓝（与血清白蛋白形成高分子复合物）的通透性。对海马毛细血管的连续切片透射电子显微镜分析显示，糖尿病会促进紧密连接的内陷、内皮细胞的窗孔形成和周细胞的退化。在其他慢性神经病理学模型中，腺苷受体 2a（Adora2a）的慢性激活会侵蚀脑血管内皮细胞之间的紧密连接，我们观察到急性 Adora2a 拮抗作用可使饮食诱导的胰岛素抵抗的野生型小鼠的 BBB 通透性正常化。在诱导性内皮细胞 Adora2a 缺失的小鼠中进行的实验表明，尽管与非转基因同窝仔鼠相比存在代谢功能障碍，但饮食诱导的胰岛素抵抗仍能保护 BBB 不破裂。对 BBB 破坏的保护与血管炎症减少、海马突触可塑性恢复和海马依赖性记忆恢复有关。这些发现表明，血管内皮细胞中 Adora2a 介导的信号转导会破坏饮食性肥胖中的 BBB，并暗示脑血管功能障碍是肥胖和胰岛素抵抗导致突触可塑性和认知功能缺陷的潜在机制。血脑屏障（BBB）限制了循环因子进入大脑，但肥胖会促进人体和动物模型中的 BBB 破坏。我们使用对 BBB 破坏具有抗性的转基因小鼠来研究神经血管功能障碍在高脂肪饮食（HFD）诱导的认知障碍中的作用。在 HFD 上，内皮细胞中诱导性缺失 Adora2a 的转基因小鼠可防止 BBB 破坏，尽管与正常小鼠相比存在类似的代谢损伤。转基因小鼠还能抵抗 HFD 引起的认知功能障碍，并能防止海马突触可塑性下降。这些发现表明，内皮细胞中 Adora2a 介导的信号转导介导肥胖引起的 BBB 破坏，并暗示脑血管功能障碍是肥胖和糖尿病导致突触可塑性和认知功能缺陷的机制。
