Characterization of ApoJ-reconstituted high-density lipoprotein (rHDL) nanodisc for the potential treatment of cerebral β-amyloidosis

Abstract

Cerebral β-amyloidosis is a major feature of Alzheimer's disease (AD), characterized by the accumulation of β-amyloid protein (Aβ) in the brain. Several studies have implicated lipid/lipoprotein metabolism in the regulation of β-amyloidosis. In this regard, HDL (High Density Lipoprotein)-based therapies could ameliorate pathological features associated with AD. As apolipoprotein J (ApoJ) is a natural chaperone that interacts with Aβ, avoiding its aggregation and toxicity, in this study we propose to prepare reconstituted rHDL-rApoJ nanoparticles by assembling phospholipids with recombinant human ApoJ (rApoJ). Hence, rHDL particles were prepared using the cholate dialysis method and characterized by N-PAGE, dynamic light scattering, circular dichroism and electron transmission microscopy. The preparation of rHDL particles showed two-sized populations with discoidal shape. Functionally, rHDL-rApoJ maintained the ability to prevent the Aβ fibrillization and mediated a higher cholesterol efflux from cultured macrophages. Fluorescently-labelled rHDL-rApoJ nanoparticles were intravenously administrated in mice and their distribution over time was determined using an IVIS Xenogen® imager. It was confirmed that rHDL-rApoJ accumulated in the cranial region, especially in old transgenic mice presenting a high cerebral Aβ load. In conclusion, we have standardized a reproducible protocol to produce rHDL-rApoJ nanoparticles, which may be potentially considered as a therapeutic option for β-amyloid-related pathologies.