期刊
ACS NANO
卷 8, 期 3, 页码 2345-2359出版社
AMER CHEMICAL SOC
DOI: 10.1021/nn4058215
关键词
reconstituted high density lipoprotein; nanomedicine; amyloid beta; apoliporpotein E; clearance; Alzheimer's disease
类别
资金
- National Natural Science Foundation of China [81373351, 81072592]
- National Key Basic Research Program [2010CB529800, 2013CB932500]
- Shanghai Science and Technology Committee [12nm0502000, 11430702200, 12ZR1416300]
- Innovation Program of Shanghai Municipal Education Commission [12ZZ107]
- National Science and Technology Major Project [2012ZX09303001-001]
- International Science & Technology Cooperation Program of China [2011DFA33180]
Amyloid-beta (A beta) 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 A beta clearance. Therefore, development of nanomedicine that can facilitate A beta 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 A beta might serve as a novel nanomedicine for disease modification in AD by accelerating A beta clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3-rHDL demonstrated high binding affinity to both A beta monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of A beta 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 A beta 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 A beta and facilitating its degradation by glial cells, indicating that ApoE3-rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating A beta clearance, which also justified the concept that nanostructures with A beta-binding affinity might provide a novel nanoplatform for AD therapy.
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