Abstract
Amyloid fibril accumulation is a pathological hallmark of several devastating disorders, including Alzheimer’s disease, prion diseases, type II diabetes, and others. Although the molecular factors responsible for amyloid pathologies have not been deciphered, interactions of misfolded proteins with cell membranes appear to play important roles in these disorders. Despite increasing evidence for the involvement of membranes in amyloid-mediated cytotoxicity, the pursuit for therapeutic strategies has focused on preventing self-assembly of the proteins comprising the amyloid plaques. Here we present an investigation of the impact of fibrillation modulators upon membrane interactions of β2-microglobulin (β2m) fibrils. The experiments reveal that polyphenols (epigallocatechin gallate, bromophenol blue, and resveratrol) and glycosaminoglycans (heparin and heparin disaccharide) differentially affect membrane interactions of β2m fibrils measured by dye-release experiments, fluorescence anisotropy of labeled lipid, and confocal and cryo-electron microscopies. Interestingly, whereas epigallocatechin gallate and heparin prevent membrane damage as judged by these assays, the other compounds tested had little, or no, effect. The results suggest a new dimension to the biological impact of fibrillation modulators that involves interference with membrane interactions of amyloid species, adding to contemporary strategies for combating amyloid diseases that focus on disruption or remodeling of amyloid aggregates.
Highlights
The transformation of soluble proteins into amyloid fibrils deposited in different organs and tissues is a hallmark of devastating medical disorders, including Alzheimer’s disease, Parkinson’s disease, type II diabetes, and others [1,2]
Plantderived polyphenols EGCG and resveratrol were tested for their impact on fibril-membrane interactions, while the synthetic polyphenol bromophenol blue was employed for comparison with these natural compounds
The results show that EGCG impairs b2m-membrane interactions, giving rise to less abundant vesicle destruction compared with giant vesicle (GV) incubated with b2m fibrils alone (compare Fig. 3, E and D(ii))
Summary
The transformation of soluble proteins into amyloid fibrils deposited in different organs and tissues is a hallmark of devastating medical disorders, including Alzheimer’s disease, Parkinson’s disease, type II diabetes, and others [1,2]. The presence of fibrillar aggregates appears to be a universal phenomenon in amyloid diseases, the relationships among amyloid formation, disease progression, and pathogenicity remain unclear. It was initially postulated that large insoluble amyloid plaques are the main culprits of the observed pathological conditions [6]. This hypothesis was challenged by findings showing that small oligomeric intermediates, rather than the endproducts of the aggregation pathway, represent the primary factors leading to cell damage and death [7,8].
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