Glutathione- and apolipoprotein E-grafted liposomes to regulate mitogen-activated protein kinases and rescue neurons in Alzheimer's disease

Abstract

Neurodegenerative disorders, such as Alzheimer's disease (AD), present biomedical challenges due to inability of pharmaceuticals to permeate the blood-brain barrier (BBB) and lack of therapeutic specificity in definite sites against multiple pathologies. Phosphatidylcholine (PC)-liposomes carrying curcumin (CURC), quercetin (QU), epigallocatechin gallate (EGCG) and rosmarinic acid (RA) with crosslinked glutathione (GSH) and apolipoprotein E (ApoE) were fabricated to recognize brain microvascular endothelial cells and amyloid beta (Aβ), and reduce tau protein hyperphosphorylation for AD management. Addition of stearic acid to liposomal bilayers ameliorated particle stability, promoted drug entrapment efficiency, and prolonged drug release duration. The triple targeting liposomes boosted the capability of CURC, QU, EGCG and RA for crossing the BBB with the assistance of grafted GSH and ApoE and docking Aβ around SK-N-MC cells using ApoE and PC. Moreover, GSH-ApoE-PC-liposomes benefited the 4 medicines in simultaneously transporting to Aβ1–42-insulted neurons, in functioning against hyperphosphorylated mitogen-activated protein kinases, including p-c-Jun N-terminal protein kinase, p-extracellular signal-regulated protein kinase 1/2 and p-p38, in downregulating tau protein at S202, caspase-3 and interleukin-6, and in upregulating p-cyclic adenosine monophosphate response element-binding protein. GSH-ApoE-PC-liposomes can be promising colloidal carriers in delivering CURC, QU, EGCG and RA to degenerated neural tissue in a controlled manner, targeting pathological factors for neuroprotection, and raising preclinical effectualness for AD treatment.