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Title: Identification of natural polyphenols and plant extracts as potent inhibitors of lipid membrane destabilisation by amyloid-beta peptide (1-42)
Authors: Gauci, Alison
Keywords: Polyphenols
Plant extracts
Lipid membranes
Amyloid beta-protein
Issue Date: 2010
Citation: Gauci A. (2010). Identification of natural polyphenols and plant extracts as potent inhibitors of lipid membrane destabilisation by amyloid-beta peptide (1-42) (Master's dissertation).
Abstract: Amyloid-beta (Aβ) aggregation is a recognised key process in the pathogenesis of Alzheimer's Disease {AD}, the most common age-related neurodegenerative disorder. Misfolded Aβ peptides self-assemble sequentially into oligomers, protofibrils and fibrils; current evidence points to oligomers as being the primary neurotoxic Aβ species, especially because they are highly disruptive to lipid membranes. Hence the aim was to explore whether small-molecule compounds and bioactive natural extracts can inhibit aggregated Aβ from damaging lipid membranes. Using a combination of fluorophore-based lipid vesicle assays, Thioflavin T assays and immunoblotting, a robust protocol for Aβ(1-42) peptide aggregation into a range of ollgomers (20-220 kDa) having 30-40% liposomal toxicity was first established. Assays using liposomes loaded with FITC-dextran molecules of different sizes confirmed that the Aβ oligomers efficiently permeabilised the vesicle membranes. Next, 15 small-molecule polyphenolic compounds, 8 N'-benzylidene-benzohydrazide (NBB) compounds, 7 diphenylpyrazole (DPP) compounds, and 4 plant extracts were assessed for their ability to antagonise liposome permeabilisation by the Aβ(1-42) oligomers. Essentially, it was found that black tea extract, apigenin, baicalein and nordihydroguaiaretic acid (NDGA) potently inhibited lipid membrane damage by aggregated Aβ to < 30% of the control value (permeabilisation caused by Aβ). Solubilised extract from the marine plant Padina pavonica, scutellarein and synthetic DPP compound nr. 15 inhibited liposome permeabilisation by Aβ aggregates to "'40%. Interestingly, apigenin, baicalein and scutellarein are flavones and both NDGA and DPP nr. 15 are symmetrical molecules of similar length having a benzene ring at each end of the molecule. Synergism was found when pairwise combinations of DPP15, apigenin and NDGA were performed. Indeed, detailed structure-function analysis of our data could assist in the identification of common chemical scaffolds for inhibition of oligomer toxicity in neurodegenerative amyloidoses.
Description: M.SC.PATHOLOGY
Appears in Collections:Dissertations - FacM&S - 2010

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