Lipoprotein-Based Nanoparticles Rescue the Memory Loss of Mice with Alzheimer's Disease by Accelerating the Clearance of Amyloid-Beta

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.