The shape effect of reconstituted high-density lipoprotein nanocarriers on brain delivery and Aβ clearance  

作　　者：Huahua Song Xinyi Ma Jianrong Xu Qingxiang Song Meng Hu Xiao Gu Qian Zhang Lina Hou Lepei Chen Yukun Huang Ping Yu Dayuan Wang Gan Jiang Meng Huang Jun Chen Hongzhuan Chen Xiaoling Gao 

机构地区：[1]Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai.liao Tong University, Shanghai 200025, China [2]Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, China [3]Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China

出　　处：《Nano Research》2018年第10期5615-5628,共14页纳米研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China （Nos. 81373351, 81573382, 81722043, and 81503174）, the National Science and Technology Major Project （No. 2018ZX09734005-007）, the National Youth Talent Support Program, grant from Shanghai Science and Technology Committee （No. 15540723700）, and ＂Shu Guang＂ project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation （No. 15SG14）.

摘　　要：Accumulation of extracellular β-amyloid （Aβ） is crucial for the pathogenesis of Alzheimer＇s disease （AD）, and the development of novel therapeutic agents that can both accelerate Aβ clearance and inhibit the subsequent pathological cascades is regarded as a promising strategy for AD management. In our previous study, we have constructed discoidal apolipoprotein E3-reconstituted high-density lipoprotein （ApoE3-rHDL） as an efficient nanoplatform that can penetrate the blood-brain barrier and accelerate Aβ clearance for a combination treatment of AD. To further improve its drug loading capacity, we hypothesized that spherical rHDL might serve as a more powerful nanocarrier if it has the same brain delivery and Aβ clearance abilities as the discoidal rHDL does. To evaluate the potential of spherical rHDL as a promising alternative for the combination therapy for AD, here, we investigated the effect of the shape of rHDL on its brain delivery, Aβ clearance, and anti-AD efficacy. We found that spherical rHDL had stronger Aβ-binding affinity than discoidal rHDL did, more effectively facilitated microglial uptake and degradation of Aβ-42, achieved better brain distribution after intravenous administration, and more powerfully reduced Aβ deposition, decreased microglia activation, attenuated neurological damage, and rescued memory deficits in a mouse model of AD. Among the rHDLs evaluated, monosialotetrahexosyl ganglioside-incorporated spherical rHDL exerted the best effect. The findings of this study for the first time show a shape effect of an rHDL nanocarrier on its biological functions and suggest that a spherical lipoprotein-mimic nanocarrier may serve as a more efficient multifunctional nanoplatforrn for AD therapy.Accumulation of extracellular β-amyloid （Aβ） is crucial for the pathogenesis of Alzheimer＇s disease （AD）, and the development of novel therapeutic agents that can both accelerate Aβ clearance and inhibit the subsequent pathological cascades is regarded as a promising strategy for AD management. In our previous study, we have constructed discoidal apolipoprotein E3-reconstituted high-density lipoprotein （ApoE3-rHDL） as an efficient nanoplatform that can penetrate the blood-brain barrier and accelerate Aβ clearance for a combination treatment of AD. To further improve its drug loading capacity, we hypothesized that spherical rHDL might serve as a more powerful nanocarrier if it has the same brain delivery and Aβ clearance abilities as the discoidal rHDL does. To evaluate the potential of spherical rHDL as a promising alternative for the combination therapy for AD, here, we investigated the effect of the shape of rHDL on its brain delivery, Aβ clearance, and anti-AD efficacy. We found that spherical rHDL had stronger Aβ-binding affinity than discoidal rHDL did, more effectively facilitated microglial uptake and degradation of Aβ-42, achieved better brain distribution after intravenous administration, and more powerfully reduced Aβ deposition, decreased microglia activation, attenuated neurological damage, and rescued memory deficits in a mouse model of AD. Among the rHDLs evaluated, monosialotetrahexosyl ganglioside-incorporated spherical rHDL exerted the best effect. The findings of this study for the first time show a shape effect of an rHDL nanocarrier on its biological functions and suggest that a spherical lipoprotein-mimic nanocarrier may serve as a more efficient multifunctional nanoplatforrn for AD therapy.

关 键 词：reconstituted high density lipoprotein Β-AMYLOID apolipoprotein E SPHERICAL discoidal Alzheimer＇s disease 

分 类 号：Q513[生物学—生物化学] TS211.41[轻工技术与工程—粮食、油脂及植物蛋白工程]