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Nano Research

Article Title

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

Authors

Huahua Song, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Xinyi Ma, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Jianrong Xu, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Qingxiang Song, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Meng Hu, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Xiao Gu, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Qian Zhang, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Lina Hou, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Lepei Chen, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Yukun Huang, Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, China
Ping Yu, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Dayuan Wang, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Gan Jiang, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Meng Huang, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Jun Chen, Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, China
Hongzhuan Chen, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
Xiaoling Gao, Department of Pharmacology and Chemical Biology, Faculty of Basic Medicine, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China

Keywords

reconstituted high density lipoprotein, β-amyloid, apolipoprotein E, spherical, discoidal, Alzheimer's disease

Abstract

ABSTRACT 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 Aβ1–42, 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 nanoplatform for AD therapy.

Graphical Abstract

Publisher

Tsinghua University Press

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