Potential inplications of endogenous aldehydes in beta-amyloid misfolding, oligomerization and fibrillogenesis.
Aldehydes are capable of inducing protein cross-linkage. An increase in aldehydes has been found in Alzheimer's disease. Formaldehyde and methylglyoxal are produced via deamination of, respectively, methylamine and aminoacetone catalyzed by semicarbazide-sensitive amine oxidase (SSAO, EC 1.4.3.6. The enzyme is located on the outer surface of the vasculature, where amyloidosis is often initiated. A high SSAO level has been identified as a risk factor for vascular disorders. Serum SSAO activity has been found to be increased in Alzheimer's patients. Malondialdehyde and 4-hydroxynonenal are derived from lipid peroxidation under oxidative stress, which is also associated with Alzheimer's disease. Aldehydes may potentially play roles in beta-amyloid aggregation related to the pathology of Alzheimer's disease. In the present study, thioflavin-T fluorometry, dynamic light scattering, circular dichroism spectroscopy and atomic force microscopy were employed to reveal the effect of endogenous aldehydes on beta-amyloid at different stages, i.e. beta-sheet formation, oligomerization and fibrillogenesis. Formaldehyde, methylglyoxal and malondialdehyde and, to a lesser extent, 4-hydroxynonenal are not only capable of enhancing the rate of formation of beta-amyloid beta-sheets, oligomers and protofibrils but also of increasing the size of the aggregates. The possible relevance to Alzheimer's disease of the effects of these aldehydes on beta-amyloid deposition is discussed.
Chen
Kun
K
Neuropsychiatry Research Unit, Department of Psychiatry, Saskatchewan Structural Sciences Centre, University of Saskatchewan, Saskatoon, Canada.
Maley
Jason
J
Yu
Peter H
PH
D000447:Aldehydes / Q000378:metabolism* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D005470:Fluorometry; D005557:Formaldehyde / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008315:Malondialdehyde / Q000378:metabolism; D018625:Microscopy, Atomic Force; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011108:Polymers / Q000378:metabolism; D017510:Protein Folding; D040901:Proteomics / Q000379:methods; D011765:Pyruvaldehyde / Q000378:metabolism; D013057:Spectrum Analysis; D013844:Thiazoles
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D015815:Cell Adhesion Molecules; D011108:Polymers; D013844:Thiazoles; D005557:Formaldehyde; C009462:thioflavin T; D008315:Malondialdehyde; D011765:Pyruvaldehyde; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse