Potential nanotherapeutic approach for Alzheimer's disease: in vitro clearance of beta-amyloid across the blood-brain barrier by multifunctional liposomes

The reduction of amyloid-beta peptides (Ab) is considered a primary therapeutic target to minimize the neurodegeneration in Alzheimer's disease (AD), a pathology characterized by accumulation of Ab in the brain. A possible strategy to reduce Ab levels is to exploit the peripheral-sink effect that is based on the removal of plasma Ab, drawing out soluble Ab from the brain. Objectives. The aim of the present study was to investigate the potential effect of multi-functional liposomes binding Ab on the peptide exchange across an in vitro model of the blood-brain barrier (BBB). Methods. Liposomes were prepared by extrusion procedure and bi-functionalized with phosphatidic acid and with a modified ApoE-derived peptide (mApoE-PA-LIP) for Ab binding. An in vitro BBB model made of human brain endothelial cells (hCMEC/D3) was set up on a transwell system and soluble small Ab42 assemblies were added to the basolateral compartment (brain side). The Ab translocation across the BBB was evaluated both alone or with mApoE-PA-LIP present in the apical compartment (blood side). Also the permeability of liposomes from basolateral-to-apical compartment in the presence of Ab was analyzed. Results. The presence of mApoE-PA-LIP strongly enhanced (5-fold) the basolateral-to-apical transcytosis of Ab across the BBB model, compared to the peptide alone, in a lipid dosedependent manner. Moreover, the transcytosis of Ab was due to a peripheral-sink effect since mApoE-PA-LIP were not able to transport the peptide across the cellular monolayer. Conclusions. This study provide a rationale for the use of Ab-binding particles as a potential therapeutic strategy for AD.