Interaction between synthetic amyloid‐β‐peptide (1–40) and its aggregation inhibitors studied by electrospray ionization mass spectrometry

Abstract

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.

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and Fe(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry

“…Although the ESI technique is widely used in studies of noncovalent complexes of biomolecules [21][22][23][24][25][26], the correspondence between the specific noncovalent complexes formed in solution and gas-phase cluster ions produced by the ESI technique may be questioned [31][32][33]. Concern has been expressed that single molecules present in the solute can be randomly distributed in the sprayed droplets and can form any possible type of associate upon desolvation of the droplets.…”

“…In order to evaluate the potential of the drugs to form noncovalent complexes with Fe(III)-heme and their relative binding strengths, we resorted to electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS). Electrospray ionization mass spectrometry provides a rapid, sensitive and highly selective tool for probing noncova- lent interactions [21][22][23][24]. Most studies that are based on this approach rely on the ability of ESI to transfer noncovalent solution-phase assemblies intact into the gas phase.…”

Insight Into the Kinetic of Amyloid β (1–42) Peptide Self‐Aggregation: Elucidation of Inhibitors’ Mechanism of Action

“…Therefore, the inhibition of toxic and soluble Ab42 aggregates has emerged as a promising approach to develop effective therapeutics for AD, and might be more effective than preventing fibril aggregation. [11][12][13][14] Abnormally increased levels of monomeric 42-residue amyloid b protein are present in the brain of patients with AD, whereas when it is produced during normal metabolism, it appears to have no deleterious effects on neurons. [15,16] Furthermore it is well established that the transition of the Ab42 secondary structure from soluble unordered/a-helix to b-sheetrich conformers [17][18][19] plays a critical role in neurodegeneration and AD progression.…”

Molecular recognition by mass spectrometry

“…ESI-MS has been applied to the study of molecules which form noncovalent complexes with amyloid-ˇ-peptides, thus showing a possible interference with the, in vitro, fibril formation. 110 Circular dichroism, electron microscopy and NMR spectroscopy studies indicate that melatonin, a hormone produced in the human brain, may inhibit the progressive formation of amyloid fibrils by interacting with amyloid-ˇ-peptides. 111 Giving support to these studies, ESI-MS reveals the actual interaction between melatonin (M 1 D 232 Da) and the amyloid-ˇ-peptide 1 -40 (M 2 D 4327 Da).…”