1. Comparison of Aβ (1-40, 1-28, 11-22, and 29-40) aggregation processes and inhibition of toxic species generated in early stages of aggregation by a water-soluble ruthenium complex
Mariana P Cali, Lorena M B Pereira, Marcio D Teodoro, Tarciso A Sellani, Elaine G Rodrigues, Rose M Carlos J Inorg Biochem. 2021 Feb;215:111314. doi: 10.1016/j.jinorgbio.2020.111314. Epub 2020 Nov 21.
Neurotoxicity of amyloid beta (Aβ) species generated in early stages of aggregation has been associated with development of Alzheimer's disease (AD). Consequently, the field of action of compounds that can identify and inhibit the formation of these species has enlarged considerably. This study investigates the effect and influence of the luminescent, water soluble metal complex cis-[Ru(phen)2(3,4Apy)2]2+ (RuApy, 3,4Apy = 3,4-diaminopyridine, phen = 1,10-phenanthroline) on the aggregation process and toxicity of Aβ1-40 and its Aβ1-28, Aβ11-22 and Aβ29-40 fragments since their early stages. The absence of correlation between the conformations generated by Aβ fragments and the full length 1-40 peptide during aggregation and the absence of toxicity of Aβ fragments to PC12 cells in all stages of aggregation indicated that the aggregation pathway and toxicity found to the full-length Aβ1-40 depends on specific interactions between the three fragments. The toxicity of Aβ1-40 was dependent on the aggregation step investigated: species generated at the beginning (15 min) of aggregation were toxic, whereas mature (120 min) fibrils were not. The RuApy complex is not toxic to PC12 cells up to 60 μM, and does not interfere with the aggregation pathway of the Aβ fragments, but interferes with the aggregation of Aβ1-40 and protects the PC12 cells, maintaining 100% of cell viability against the toxicity of Aβ1-40 species generated in early stages of aggregation.
2. Effect of trehalose on amyloid beta (29-40)-membrane interaction
Allam S Reddy, Aslin Izmitli, J J de Pablo J Chem Phys. 2009 Aug 28;131(8):085101. doi: 10.1063/1.3193726.
A growing body of experimental evidence indicates that the interaction between amyloid beta peptide and lipid bilayer membranes plays an important role in the development of Alzheimer disease. Recent experimental evidence also suggests that trehalose, a simple disaccharide, reduces the toxicity of amyloid beta peptide. Molecular simulations are used to examine the effect of trehalose on the conformational stability of amyloid beta peptide in aqueous solution and its effect on the interaction between amyloid beta peptide and a model phospholipid bilayer membrane. It is found that, in aqueous solution, the peptide exhibits a random coil conformation but, in the presence of trehalose, it adopts an alpha helical conformation. It is then shown that the insertion of amyloid beta peptide into a membrane is more favorable when the peptide is folded into an alpha-helix than in a random coil conformation, thereby suggesting that trehalose promotes the insertion of alpha-helical amyloid beta into biological membranes.
3. Interaction between synthetic amyloid-beta-peptide (1-40) and its aggregation inhibitors studied by electrospray ionization mass spectrometry
Z Skribanek, L Baláspiri, M Mák J Mass Spectrom. 2001 Nov;36(11):1226-9. doi: 10.1002/jms.243.
It is generally postulated that amyloid-beta-peptides play a central role in the progressive neurodegeneration observed in Alzheimer's disease. Important pathological properties of these peptides, such as neurotoxicity and resistance to proteolytic degradation, depend on the ability of amyloid-beta-peptides to form beta-sheet structures and/or amyloid fibrils. Amyloid-beta-peptides are known to aggregate spontaneously in vitro with the formation of amyloid fibrils. The intervention on the amyloid-beta-peptides aggregation process can be envisaged as an approach to stopping or slowing the progression of Alzheimer's disease. In the last few years a number of small molecules have been reported to interfere with the in vitro aggregation of amyloid-beta-peptides. Melatonin, a hormone recently found to protect neurons against amyloid-beta-peptide toxicity, interacts with amyloid-beta-peptide (1-40) and amyloid-beta-peptide (1-42) and inhibits the progressive formation of beta-sheet and/or amyloid fibrils. These interactions between melatonin and the amyloid peptides have been demonstrated by circular dichroism (CD) and electron microscopy for amyloid-beta-peptide (1-40) and amyloid-beta-peptide (1-42) and by nuclear magnetic resonance (NMR) spectroscopy for amyloid-beta-peptide (1-40). Our electrospray ionization mass spectrometric (ESI-MS) studies also proved that there is a hydrophobic interaction between amyloid-beta-peptide (1-40) and melatonin and the proteolytic investigations suggested that the interaction took place on the 29-40 amyloid-beta-peptide segment. The wide-ranging application of these results would provide further information and help in biological research.