Abstract
BackgroundLipofuscin (LF) is formed during lipid peroxidation and sugar glycosylation by carbonyl-amino crosslinks with biomacrolecules, and accumulates slowly within postmitotic cells. The environmental pollution, modern dietary culture and lifestyle changes have been found to be the major sources of reactive carbonyl compounds in vivo. Irreversible carbonyl-amino crosslinks induced by carbonyl stress are essentially toxiferous for aging-related functional losses in modern society. Results show that (-)-epigallocatechin gallate (EGCG), the main polyphenol in green tea, can neutralize the carbonyl-amino cross-linking reaction and inhibit LF formation, but the underlying mechanism is unknown.Methods and ResultsWe explored the mechanism of the neutralization process from protein, cell, and animal levels using spectrofluorometry, infrared spectroscopy, conformation antibodies, and electron microscopy. LF demonstrated an amyloidogenic β-sheet-rich with antiparallel structure, which accelerated the carbonyl-amino crosslinks formation and disrupted proteolysis in both PC12 cells and D-galactose (D-gal)-induced brain aging mice models. Additionally, EGCG effectively inhibited the formation of the amyloidogenic β-sheet-rich structure of LF, and prevented its conversion into toxic and on-pathway aggregation intermediates, thereby cutting off the carbonyl-amino crosslinks.ConclusionsOur study indicated that the amyloidogenic β-sheet structure of LF may be the core driving force for carbonyl-amino crosslinks further formation, which mediates the formation of amyloid fibrils from native state of biomacrolecules. That EGCG exhibits anti-amyloidogenic β-sheet-rich structure properties to prevent the LF formation represents a novel strategy to impede the development of degenerative processes caused by ageing or stress-induced premature senescence in modern environments.
Highlights
Lipofuscin (LF) is a brownish-yellow, electron-dense, and autofluorescent material that accumulates progressively with aging in postmitotic cells, such as in neurons, skeletal muscle cells, cardiac myocytes and retinal pigment epithelium
We explored the mechanism of the neutralization process from protein, cell, and animal levels using spectrofluorometry, infrared spectroscopy, conformation antibodies, and electron microscopy
Our study indicated that the amyloidogenic β-sheet structure of LF may be the core driving force for carbonyl-amino crosslinks further formation, which mediates the formation of amyloid fibrils from native state of biomacrolecules
Summary
Lipofuscin (LF) is a brownish-yellow, electron-dense, and autofluorescent material that accumulates progressively with aging in postmitotic cells, such as in neurons, skeletal muscle cells, cardiac myocytes and retinal pigment epithelium. The reactive carbonyl compounds of lipid peroxidation and sugar glycosylation induce misfolded carbonyl-amino crosslinks by binding with biomacrolecules and further form LF [1]. Compared with oxidation products of proteins (ceroid), lipofuscin accumulates more slowly within postmitotic cells, and is more resistant to digestion. Using both free radical scavengers and antioxidants is inefficient on pre-formed reactive carbonyl compounds. Previous studies show that the ability of inhibition of proteasomal activity is not significantly altered by chemically reducing carbonyls on the LF surface [10] This characteristic indicates that carbonyl toxicity is not the only toxic factor of LF. Results show that (-)-epigallocatechin gallate (EGCG), the main polyphenol in green tea, can neutralize the carbonyl-amino cross-linking reaction and inhibit LF formation, but the underlying mechanism is unknown
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