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Shape effect of Reconstituted High-Density Lipoprotein Nanocarriers on Brain delivery and Aβ Clearance

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  
【摘要】:The accumulation of extracellular β-amyloid(Aβ) is crucial in 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 has been taken as a promising strategy for AD management.Our previous work has constructed discoidal apolipoprotein E3-reconstituted high-density lipoprotein(ApoE3-rHDL) as an efficient nanoplatform that could penetrate the blood-brain barrier(BBB) and accelerate Aβ clearance for the combination therapy of AD.To further improve its drug loading capacity,we proposed that spherical rHDL might serve as a more powerful nanocarrier if it owns the same brain delivery and Aβclearance abilities as the discoidal rHDL.To evaluate the potential of spherical rHDL as a promising alternative for the combination therapy of AD,here we investigated the effect of shape of rHDL on its brain delivery,Aβ clearance and anti-AD efficacy.We found that spherical rHDL illustrated higher Aβ binding affinity than discoidal rHDL,more efficiently facilitated microglia uptake and degradation of Aβ_(1-42),achieved higher brain distribution following intravenous administration,and more powerfully reduced Aβ deposition,decreased microglia-activation,attenuated neurological damage,and rescued memory deficits in AD model mice,among which monosialotetrahexosyl ganglioside-incorporated spherical rHDL exhibited the best effect.The findings of this work firstly demonstrated the shape effect of rHDL nanocarrier on its biological functions and suggested that spherical lipoprotein-mimic nanocarrier might serve as a more efficient multi-functional nanoplatform for AD therapy.

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