Zhang Qian, Song Qingxiang, Gu Xiao, Zheng Mengna, Wang Antian, Jiang Gan, Huang Meng, Chen Huan, Qiu Yu, Bo Bin, Tong Shanbao, Shao Rong, Li Binyin, Wang Gang, Wang Hao, Hu Yongbo, Chen Hongzhuan, Gao Xiaoling
Department of Pharmacology and Chemical Biology State Key Laboratory of Oncogenes and Related Genes Shanghai Universities Collaborative Innovation Center for Translational Medicine Shanghai Jiao Tong University School of Medicine 280 South Chongqing Road Shanghai 200025 China.
School of Biomedical Engineering and Med-X Research Institute Shanghai Jiao Tong University 800 Dongchuan Road Shanghai 200240 China.
Adv Sci (Weinh). 2020 Dec 10;8(2):2001918. doi: 10.1002/advs.202001918. eCollection 2021 Jan.
Cerebrovascular dysfunction characterized by the neurovascular unit (NVU) impairment contributes to the pathogenesis of Alzheimer's disease (AD). In this study, a cerebrovascular-targeting multifunctional lipoprotein-biomimetic nanostructure (RAP-RL) constituted with an antagonist peptide (RAP) of receptor for advanced glycation end-products (RAGE), monosialotetrahexosyl ganglioside, and apolipoprotein E3 is developed to recover the functional NVU and normalize the cerebral vasculature. RAP-RL accumulates along the cerebral microvasculature through the specific binding of RAP to RAGE, which is overexpressed on cerebral endothelial cells in AD. It effectively accelerates the clearance of perivascular A, normalizes the morphology and functions of cerebrovasculature, and restores the structural integrity and functions of NVU. RAP-RL markedly rescues the spatial learning and memory in APP/PS1 mice. Collectively, this study demonstrates the potential of the multifunctional nanostructure RAP-RL as a disease-modifying modality for AD treatment and provides the proof of concept that remodeling the functional NVU may represent a promising therapeutic approach toward effective intervention of AD.
以神经血管单元（NVU）损伤为特征的脑血管功能障碍促成了阿尔茨海默病（AD）的发病机制。在本研究中，一种由晚期糖基化终产物受体（RAGE）的拮抗剂肽（RAP）、单唾液酸四己糖神经节苷脂和载脂蛋白E3构成的脑血管靶向多功能脂蛋白仿生纳米结构（RAP-RL）被开发出来，以恢复功能性NVU并使脑血管系统正常化。RAP-RL通过RAP与RAGE的特异性结合沿着脑微血管系统聚集，RAGE在AD的脑内皮细胞上过度表达。它有效地加速了血管周围Aβ的清除，使脑血管系统的形态和功能正常化，并恢复了NVU的结构完整性和功能。RAP-RL显著挽救了APP/PS1小鼠的空间学习和记忆能力。总体而言，本研究证明了多功能纳米结构RAP-RL作为AD治疗的疾病修饰方式的潜力，并提供了概念验证，即重塑功能性NVU可能是有效干预AD的一种有前景的治疗方法。
