Affiliation:
1. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
2. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China
Abstract
The disequilibrium of amyloid β-peptide (Aβ) between the central and peripheral pools has been claimed as an initiating event in Alzheimer’s disease (AD). In this study, we employ discoidal high-density lipoproteins (HDL-Disc) mimicking Aβ antibody for directional flux of Aβ from central to peripheral catabolism, with desirable safety and translation potential. Structurally, HDL-Disc assembly (polyDisc) is prepared with aid of chitosan derivative polymerization. After intranasal administration and response to slightly acidic nasal microenvironment, polyDisc depolymerizes into carrier-free HDL-Disc with chitosan derivatives that adhere to the mucosal layer to reversibly open tight junctions, helping HDL-Disc penetrate the olfactory pathway into brain. Thereafter, HDL-Disc captures Aβ into microglia for central clearance or ferries Aβ out of the brain for liver-mediated compensatory catabolism. For synergy therapy, intranasal administration of polyDisc can effectively reduce intracerebral Aβ burden by 97.3% and vascular Aβ burden by 73.5%, ameliorate neurologic damage, and rescue memory deficits in APPswe/PS1dE9 transgenic AD mice with improved safety, especially vascular safety. Collectively, this design provides a proof of concept for developing Aβ antibody mimics to mobilize a synergy of central and peripheral Aβ clearance for AD treatment.
Funder
MOST | National Natural Science Foundation of China
Publisher
Proceedings of the National Academy of Sciences