Lipid-dependent production of neurotoxic Abeta protofibrils from fibrils

Abstract

While soluble oligomeric and protofibrillar assemblies of Aβ-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's Disease (AD), the role of mature Aβ-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillisation reaction proceeds forward from the monomeric Ab peptide through toxic protofibrillar intermediates which further mature into the amyloid fibrils that are found in plaques, and which are thought to be stable and biologically inert. Using a combination of biophysical methods, cell biological studies and behavioural studies on mice we here investigate the effect of biological lipids on the stability and cytotoxicity of mature Abeta amyloid fibrils. We show that natural lipids can rapidly induce fiber destabilization and resolubilization. Interestingly, the equilibrium is not reversed towards monomeric Aβ but rather towards the soluble amyloid protofibrils, which we thus call backward protofibrils to distinguish from the species obtained during the “forward” aggregation process of monomeric Aβ42. Backward protofibrils are biochemically and biophysically very similar to forward protofibrils; They consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain and accumulate in areas relevant to AD. Our findings suggest that amyloid plaques are potentially major sources of toxic Abeta-aggregates that can be activated by changes in physiological conditions such as the presence of free lipids.