Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach.
Vaccination against human beta-amyloid peptide (A beta) has been shown to remove the amyloid burden produced in transgenic mice overexpressing the mutated human amyloid precursor protein (APP) gene. For human beings, the efficiency of this therapeutic strategy has to take into account the specificities of human amyloid, especially at the early stages of 'sporadic' Alzheimer's disease (AD). A beta 40/42 were previously quantified in tissues from our well-established brain bank, including non-demented individuals with both mild amyloid and tau pathologies, hence corresponding to the earliest stages of Alzheimer pathology. Herein, we have adapted a proteomic method combined with western blotting and mass spectrometry for the characterization of insoluble A beta extracted in pure-formic acid. We demonstrated that amino-truncated A beta species represented more than 60% of all A beta species, not only in full blown AD, but also, and more interestingly, at the earliest stage of Alzheimer pathology. At this stage, A beta oligomers were exclusively made of A beta-42 species, most of them being amino-truncated. Thus, our results strongly suggest that amino-truncated A beta-42 species are instrumental in the amyloidosis process. In conclusion, a vaccine specifically targeting these pathological amino-truncated species of A beta-42 are likely to be doubly beneficial, by inducing the production of specific antibodies against pathological A beta products that are, in addition, involved in the early and basic mechanisms of amyloidosis in humans.
Sergeant
Nicolas
N
INSERM U422, Groupe VCDN, Equipe Protéomique, Lille, France.
Bombois
Stepanie
S
Ghestem
Antoine
A
Drobecq
Hervé
H
Kostanjevecki
Vesna
V
Missiaen
Carla
C
Wattez
Annick
A
David
Jean-Phillipe
JP
Vanmechelen
Eugeen
E
Sergheraert
Christian
C
Delacourte
André
A
D000544:Alzheimer Disease / Q000276:immunology / Q000628:therapy; D023582:Alzheimer Vaccines / Q000276:immunology / Q000592:standards; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology; D015153:Blotting, Western; D001923:Brain Chemistry; D018450:Disease Progression; D015180:Electrophoresis, Gel, Two-Dimensional; D005561:Formates / Q000737:chemistry; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry; D012016:Reference Values; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D005561:Formates; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C030544:formic acid