title: Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer's disease by accelerating the clearance of amyloid-beta.
abstract: Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer's disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically inspired nanostructure, apolipoprotein E3-reconstituted high density lipoprotein (ApoE3-rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3-rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3-rHDL gained access to the brain. Four-week daily treatment with ApoE3-rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes, and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of a biomimetic nanostructure crossing the blood-brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3-rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy.
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine , 280 South Chongqing Road, Shanghai 200025, PR China.
authors: Qingxiang
authors: Q
authors: Song
authors: Meng
authors: M
authors: Huang
authors: Lei
authors: L
authors: Yao
authors: Xiaolin
authors: X
authors: Wang
authors: Xiao
authors: X
authors: Gu
authors: Juan
authors: J
authors: Chen
authors: Jun
authors: J
authors: Chen
authors: Jialin
authors: J
authors: Huang
authors: Quanyin
authors: Q
authors: Hu
authors: Ting
authors: T
authors: Kang
authors: Zhengxing
authors: Z
authors: Rong
authors: Hong
authors: H
authors: Qi
authors: Gang
authors: G
authors: Zheng
authors: Hongzhuan
authors: H
authors: Chen
authors: Xiaoling
authors: X
authors: Gao
mesh_terms: D000544:Alzheimer Disease / Q000150:complications*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000378:metabolism; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D050997:Nanomedicine; D053758:Nanoparticles; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D008075:Lipoproteins, HDL