Abstract
Due to an aging population, neurodegenerative diseases such as Alzheimer’s disease (AD) have become a major health issue. In the case of AD, Aβ1–42 peptides have been identified as one of the markers of the disease with the formation of senile plaques via their aggregation, and could play a role in memory impairment and other tragic syndromes associated with the disease. Many studies have shown that not only the morphology and structure of Aβ1–42 peptide assembly are playing an important role in the formation of amyloid plaques, but also the interactions between Aβ1–42 and the cellular membrane are crucial regarding the aggregation processes and toxicity of the amyloid peptides. Despite the increasing amount of information on AD associated amyloids and their toxicity, the molecular mechanisms involved still remain unclear and require in-depth investigation at the local scale to clearly decipher the role of the sequence of the amyloid peptides, of their secondary structures, of their oligomeric states, and of their interactions with lipid membranes. In this original study, through the use of Atomic Force Microscopy (AFM) related-techniques, high-speed AFM and nanoInfrared AFM, we tried to unravel at the nanoscale the link between aggregation state, structure and interaction with membranes in the amyloid/membrane interaction. Using three mutants of Aβ peptides, L34T, oG37C, and WT Aβ1–42 peptides, with differences in morphology, structure and assembly process, as well as model lipidic membranes whose composition and structure allow interactions with the peptides, our AFM study coupling high spatial and temporal resolution and nanoscale structure information clearly evidences a local correlation between the secondary structure of the peptides, their fibrillization kinetics and their interactions with model membranes. Membrane disruption is associated to small transient oligomeric entities in the early stages of aggregation that strongly interact with the membrane, and present an antiparallel β-sheet secondary structure. The strong effect on membrane integrity that exists when these oligomeric Aβ1–42 peptides interact with membranes of a particular composition could be a lead for therapeutic studies.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease associated with progressive memory loss and dementia
Our observations show a correlation between secondary structure of the peptide, fibrillization kinetics and interaction with membranes
At day 7 the fibers obtained for the wild type (WT) (Figure 2F) are thicker and shorter than the L34T ones, and assemble majoritarily into bundles of twisted short fibers, in accordance with literature (Fitzpatrick et al, 2013; Nirmalraj et al, 2020), though occasional single fibers are observed
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease associated with progressive memory loss and dementia. Two types of abnormal amyloid aggregates are found in the patient’s brains, extracellular Amyloid β plaques containing Aβ peptides and intracellular neurofibrillatory tangles (NFT) composed of hyperphosphorylated Tau protein. Both are involved in a complex cascade of events leading to synapse dysfunction and neuronal death. As the major component of these plaques, the 42 amino-acid long amyloid peptide Aβ1-42 has been shown to be neurotoxic (Yasumoto et al, 2019) playing a role in the memory impairment and the other tragic syndromes associated with the disease. An overwhelming body of evidence in in vitro (Henry et al, 2015; Yasumoto et al, 2019) and in vivo (Fruhmann et al, 2018; Yasumoto et al, 2019) studies has highlighted the importance of Aβ1-42/membrane interactions and the crucial role that lipid bilayers play regarding fibrillogenesis and toxicity (Williams and Serpell, 2011)
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