Casein-loaded proteoliposomes: novel delivery strategy to inhibit Aβ1-40 fibrillogenesis in Alzheimer disease

Abstract

Background: Alzheimer's disease (AD) is a chronic and progressive syndrome, which represents the most common cause of dementia worldwide. A pathological and characteristic AD hallmark is the deposition of amyloid plaques, composed by well-ordered amyloid β-peptide (Aβ) fibers, in brain tissue. The Aβ aggregation process follows typical nucleation-polymerization kinetics, characterized by structural intermediates with specific dimensions, morphologies and cytotoxic activity. Some evidences shifted researchers’ attention to smaller soluble Aβ prefibrillar oligomers as they result the most toxic species. Therefore, novel therapeutic strategies target oligomers or prefibrillar aggregates rather than mature fibers. In particular, αs1-Casein, a natural bovine milk protein, resulted able to slow down the entire fibrillogenesis process, increase the lag-time of the nucleation phase and sequester the Aβ peptide on its surface[1]. Future perspectives and scope: to benefit from the remarkable therapeutic option represented by αs1-Casein in AD treatment, it is crucial to define a way to efficiently protect proteins and deliver them to the brain in appropriate amounts. Liposomes are spherical phospholipids-based vesicles characterized by excellent biocompatibility and biodegradability, low toxicity, ability to incorporate and protect both hydrophilic and hydrophobic drugs as well as ability to cross the Blood-Brain Barrier (BBB) in order to access the CNS. Based on these considerations, novel proteoliposomes composed by phospholipids, cholesterol and αs1-Casein were prepared in order to exploit the potentiality of liposomes in brain delivery together with the fibrillogenesis inhibition activity of αs1-Casein. The proteoliposome preparation protocol was optimized in order to obtain the best results in terms of protein-loading and stability. Nanosystems have been characterized by different biophysics techniques, such as light scattering, zeta-potential, circular dichroism, fluorescence and AFM imaging.