A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included Nemo^Fl controls and three Nemo^beKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in Nemo^beKO mice and were not countered by treatments. Cerebrovascular function was compromised in Nemo^beKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. Nemo^beKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.

疾病发作早期发生的血管损伤可能引发认知能力下降，导致痴呆，而药物和生活方式干预可以预防这种进展。研究人员将脑内皮细胞中 NF-κB 必需调节剂 (Nemo) 选择性、他莫昔芬诱导缺失的小鼠作为血管性认知障碍模型进行了研究。各组包括 Nemo ^F1对照组和三个 Nemo ^beKO组：一组未经治疗，两组接受辛伐他汀或运动治疗。 Nemo ^beKO小鼠的社会偏好和筑巢受到损害，并且无法通过治疗来抵消。无论治疗如何，Nemo ^beKO组的脑血管功能均受到损害，感觉诱发的脑血流量和总血红蛋白水平变化减少，内皮依赖性血管舒张受损。 Nemo ^beKO小鼠的弦血管病理、血脑屏障破坏、神经炎症增加，并且含有皮质生长抑素的中间神经元减少。当内皮功能恢复时，这些改变被逆转。研究结果强烈表明，脑内皮损伤可能引发与痴呆症相关的病理，其功能完整性应该成为未来治疗工作的有效目标。