The shape effect of reconstituted high-density lipoprotein nanocarriers on brain delivery and Aβ clearance
reconstituted high density lipoprotein, β-amyloid, apolipoprotein E, spherical, discoidal, Alzheimer's disease
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.
Tsinghua University Press
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, The shape effect of reconstituted high-density lipoprotein nanocarriers on brain delivery and Aβ clearance. NanoRes.2018, 11(10): 5615–5628