Attenuated amyloid-beta aggregation and neurotoxicity owing to methionine oxidation.
Aggregation of the amyloid-beta (Abeta) peptide into amyloid plaques is a characteristic feature of Alzheimer's disease neuropathogenesis. We and others have previously demonstrated delayed Abeta aggregation as a consequence of oxidizing a single methionine residue at position 35 (Met-35). Here, we examined the consequences of Met-35 oxidation on the extremely aggregation-prone peptides Abeta1-42 and Abeta1-40Arctic with respect to protofibril and oligomer formation as well as neurotoxicity. Size exclusion chromatography and mass spectrometry demonstrated that monomer/dimers prevailed over larger oligomers after oxidizing Met-35, and consequently protofibril formation and aggregation of both Abeta1-42 and Abeta1-40Arctic were delayed. The oxidized peptides completely lacked neurotoxic effects in cortical neuronal cultures under these conditions, in contrast to the neurotoxic properties of the unoxidized peptides. We conclude that oxidation of Met-35 significantly attenuates aggregation of Abeta1-42 and Abeta1-40Arctic, and thereby reduces neurotoxicity.
Johansson
Ann-Sofi
AS
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Bergquist
Jonas
J
Volbracht
Christiane
C
Päiviö
Anna
A
Leist
Marcel
M
Lannfelt
Lars
L
Westlind-Danielsson
Anita
A
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D019281:Dimerization; D005260:Female; D013058:Mass Spectrometry; D008715:Methionine / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D011247:Pregnancy; D013454:Sulfoxides / Q000737:chemistry / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D013454:Sulfoxides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D008715:Methionine