Abstract
Amyloid-beta peptides (Aβ), implicated in Alzheimer’s disease (AD), interact with the cellular membrane and induce amyloid toxicity. The composition of cellular membranes changes in aging and AD. We designed multi-component lipid models to mimic healthy and diseased states of the neuronal membrane. Using atomic force microscopy (AFM), Kelvin probe force microscopy (KPFM) and black lipid membrane (BLM) techniques, we demonstrated that these model membranes differ in their nanoscale structure and physical properties, and interact differently with Aβ1–42. Based on our data, we propose a new hypothesis that changes in lipid membrane due to aging and AD may trigger amyloid toxicity through electrostatic mechanisms, similar to the accepted mechanism of antimicrobial peptide action. Understanding the role of the membrane changes as a key activating amyloid toxicity may aid in the development of a new avenue for the prevention and treatment of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease which leads to severe impairment of memory and cognitive function and is characterized by the formation of amyloid-beta (Aβ) protein aggregates on neurons and cerebral blood vessels[1, 2]
Lipid composition of model systems mimicking healthy and AD membrane states Though there have been numerous studies on the interaction of lipid monolayers and membranes with Aβ[6, 8, 12, 13, 26,27,28,29,30,31, 44], many studies are carried out using simple models, consisting of one to three lipid types, which do not provide a good model for neuronal membrane
Based on previous studies on the composition of the outer leaflet of the neuronal membrane[6, 20, 35, 39], we designed three different multicomponent lipid models consisting of DPPC, POPC, sphingomyelin (SM), cholesterol (Chol), and ganglioside monosialotetrahexosylganglioside (GM1), which mimic healthy and AD neuronal membranes
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease which leads to severe impairment of memory and cognitive function and is characterized by the formation of amyloid-beta (Aβ) protein aggregates on neurons and cerebral blood vessels[1, 2]. While all amyloid aggregates such as oligomers, fibrils, and plaques serve as cellular hallmarks of AD, small soluble oligomers have recently been shown to be more toxic to cells than larger fibrils[3]. In this work we propose and test a new hypothesis that changes in lipid membrane structure and properties may trigger amyloid toxicity. It is known that Aβ aggregation occurs on the surfaces of neuronal cells, leading to amyloid plaque formation in the brain tissues of individuals diagnosed with AD[1, 2]. Aβ-membrane interactions may occur through specific membrane receptors[4] as well as non- with the lipid
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