Wang Jingyuan, Wang Zekun, Li Yuqing, Hou Yajun, Yin Chenyang, Yang Endong, Liao Ziyu, Fan Cundong, Martin Lisandra L, Sun Dongdong
School of Life Sciences, Anhui Agricultural University, Hefei, Anhui, 230036, China.
Department of Neurology, The Second Affiliated Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, Shandong, China.
Biomaterials. 2023 Oct 22;302:122359. doi: 10.1016/j.biomaterials.2023.122359.
Alzheimer's disease (AD) as a common neurodegenerative disease showed progressive cognitive dysfunction and behavioral impairment. Currently, the deposition of amyloid β-protein (Aβ) remains the main pathomechanism. However, preventing neuronal death induced by Aβ remains elusive, and no effective strategy in clinic was found to combat AD. Herein, a multifunctional double selenium nanosphere (CLNDSe) was designed and prepared, and AAR agonist (CGS) modification endowed CLNDSe NPs with AAR-targeted blood brain barrier (BBB) delivery in vitro and in vivo. CLNDSe NPs after modification of LPFFD short peptide effectively inhibited Aβ aggregation and attenuated Aβ-induced neural toxicity by inhibiting oxidative damage and mitochondrial dysfunctions. Nerve growth factor (NGF) linked to large Se sphere significantly attenuated Tau phosphorylation and gliocytes activation in APP/PS1 mice. CLNDSe NPs administration in vivo also effectively restored GPX1/4 antioxidant ability, alleviated neural loss and neurofibrillary tangles, prevented neural ferroptosis, and eventually ameliorated cognitive deficits of APP/PS1 mice. Importantly, CLNDSe NPs showed good safety and biocompatibility. Taken together, our finding validated the rational design that BBB-targeted delivery of double selenium nanosphere may be a novel strategy to ameliorate Alzheimer's disease by inhibiting neural ferroptosis.
阿尔茨海默病（AD）作为一种常见的神经退行性疾病，表现出进行性认知功能障碍和行为损害。目前，淀粉样β蛋白（Aβ）沉积仍然是主要的发病机制。然而，预防Aβ诱导的神经元死亡仍然难以实现，临床上尚未发现有效的抗AD策略。在此，设计并制备了一种多功能双硒纳米球（CLNDSe），AAR激动剂（CGS）修饰赋予CLNDSe纳米颗粒在体外和体内AAR靶向血脑屏障（BBB）递送的能力。LPFFD短肽修饰后的CLNDSe纳米颗粒通过抑制氧化损伤和线粒体功能障碍，有效抑制Aβ聚集并减轻Aβ诱导的神经毒性。与大硒球相连的神经生长因子（NGF）显著减轻了APP/PS1小鼠的Tau磷酸化和胶质细胞活化。CLNDSe纳米颗粒体内给药还有效恢复了GPX1/4抗氧化能力，减轻了神经损失和神经原纤维缠结，预防了神经铁死亡，并最终改善了APP/PS1小鼠的认知缺陷。重要的是，CLNDSe纳米颗粒表现出良好的安全性和生物相容性。综上所述，我们的研究结果验证了合理的设计，即双硒纳米球的血脑屏障靶向递送可能是一种通过抑制神经铁死亡来改善阿尔茨海默病的新策略。
