Zhang Biyue, Zhang Shumei, Guo Zeming, Hong Chunzhan, Zhang Futian, Lin Huasong
Department of Neurology, the Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, 362000, China.
Department of Implant Dentistry III, Stomatological Hospital of Xiamen Medical College, Xiamen, Fujian, 361006, China.
Transl Psychiatry. 2025 Sep 3;15(1):341. doi: 10.1038/s41398-025-03528-8.
Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ. Notably, NF-1 reduced oligomerized Aβ-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.
细胞衰老及相关的内皮通透性是包括阿尔茨海默病（AD）在内的神经退行性疾病中血脑屏障（BBB）功能障碍的关键因素。Nesfatin-1（NF-1）是一种参与调节食欲和能量稳态的神经肽，其在AD中的病理生理作用尚未得到广泛研究。在本研究中，我们发现NF-1处理通过恢复hTERT和TERF2的表达来改善脑微血管内皮bEnd.3细胞对抗寡聚化Aβ诱导的细胞衰老。此外，NF-1降低了暴露于寡聚化Aβ的bEnd.3细胞中p53和p21蛋白水平。值得注意的是，NF-1通过维持跨内皮电阻（TEER）以及紧密连接蛋白claudin 5和ZO-1的水平，降低了寡聚化Aβ诱导的内皮单层通透性。此外，NF-1抑制了暴露于寡聚化Aβ的bEnd.3细胞中VEGF-R1的表达，但不影响VEGF-R2的表达。VEGF-R1的过表达消除了NF-1对寡聚化Aβ诱导的细胞衰老的保护作用，并增加了内皮单层通透性，表明VEGF-R1参与了这一过程。使用转基因（Tg APPswe/PSEN1dE9）AD小鼠模型，我们证明NF-1给药降低了AD小鼠大脑皮层中VEGF-R1的表达。此外，NF-1减轻了BBB功能障碍，并增强了AD小鼠大脑中claudin 5和ZO-1的表达。我们的结果表明，NF-1可能是治疗AD潜在的治疗策略。
