AMNEsIA · Interactions of amyloid peptides with the neuronal membrane interface: molecular mechanisms involved in Alzheimer’s disease

Interactions of amyloid peptides with the neuronal membrane interface: molecular mechanisms involved in Alzheimer’s disease

Alzheimer’s disease (AD) is a common neurodegenerative disease leading to loss of cognitive functions and dementia. With an aging population, Europe alone counts over 7 million people suffering from AD, making it a critical public health issue. AD is characterized by the presence of 2 types of amyloid peptides: Aβ, found in extracellular plaques, and Tau, found in intracellular aggregates. During the development of the disease, both self-aggregating proteins are involved in a complex cascade of events leading to neuronal dysfunction and death. The neuronal membrane has been identified as a target of amyloid-induced toxicity, yet the mechanisms involved remain elusive and require investigation at the local scale. The general objective of the AMNEsIA project was to unravel the deleterious effects of AD-associated amyloid peptides on the neuronal membrane in order to better understand the underlying mechanisms of AD. To that end, we used Atomic Force Microscopy (AFM), a powerful biophysical technique that provided high-resolution information on the amyloid morphology, as well as the amyloid-induced structural changes on the neuronal membrane. We also addressed the amyloid / membrane interaction on a molecular level and investigated the mechanism of interaction. We exploited the high temporal resolution of AFM imaging, in collaboration with the Laboratory of Research in Nanosciences (University of Reims, France), to assess the effects of an oligomeric toxic variant of Aβ on model membranes of controlled lipid compositions mimicking the external neuronal membrane. Our results revealed a strong impact of the lipid composition and allowed us to propose a mechanism for the oligomeric Aβ / membrane interaction. The simultaneous presence of cholesterol and ganglioside GM1 was required in the membrane to observe its fast amyloid-induced dissolution through detergent effect. In parallel, we investigated the interaction of a Tau fragment with model membranes mimicking the inner neuronal membrane. Our data highlighted a preferential role of negatively charged lipids (POPS, PIP2) in the Tau / membrane interaction, with lipid-induced aggregation of the peptide. In addition, we have successfully initiated functionalization experiments, where we attach amyloid peptides on AFM tips in order to directly probe the amyloid peptide / membrane interaction by force spectroscopy. We also initiated the development of an incubator-like chamber with controlled environmental parameters, which will allow maintaining experimental conditions close to biological relevance. In brief, AMNEsIA has contributed to deepening our understanding of AD-associated amyloid peptides, and has laid the foundations to go further in future molecular and live cell studies.

Data: CORDIS, © European Union