Alzheimer's: Structural properties of complex model membranes after interaction with beta-amyloid peptides open the way to the identification of new drug targets

A collaboration between the department of Medical Biotechnologies and Translational Medicine at the University of Milano, the department of Molecular Biochemistry and Pharmacology at the Institut for Pharmacological Research Mario Negri in Milano and the Institut Laue-Langevin (ILL) in Grenoble, revealed the existence and extent of interaction between different Aβ(1-42) peptides and single complex biomimetic membranes. The membrane, asymmetrically containing phospholipids, GM1 and cholesterol in biosimilar proportion, is a model for a raft, a putative site for amyloid-cell membrane interaction. Neutron reflectivity experiments revealed that the interaction with membranes depends on peptide aggregative state.

The research reveals that the structured-oligomer of Aβ(1-42), its most acknowledged membrane-active state, is embedded as such into the external leaflet of the membrane. Conversely, the Aβ(1-42) unstructured early-oligomers deeply penetrate the membrane, likely mimicking the interaction at neuronal cell surfaces, when the Aβ(1-42) is cleaved from APP protein (Amyloid Precursor Protein) and the membrane constitutes a template for its further structural evolution. Moreover, the smaller Aβ(1-6) fragment, the N-terminal portion of Aβ, was also used. Aβ N-terminal is usually considered as involved in oligomer stabilization but not in the peptide-membrane interaction. Instead, it was seen to remove lipids from the bilayer, thus suggesting its role, once in the whole peptide, in membrane leakage, favouring peptide recruitment.

Together with the known ability of seeds, formed by small peptide aggregates, in driving Aβ recruitment towards fiber formation, this new vision potentially enables us to identify new drug targets.

Given over 9.9 million new cases of dementia are appearing each year worldwide, furthering research into Alzheimer's Disease has never been more important. The aims of the study therefore highlight the impact of developing synergistic interdisciplinary research collaborations.