Truncated beta-amyloid peptide species in pre-clinical Alzheimer's disease as new targets for the vaccination approach

Vaccination against human beta-amyloid peptide (Abeta) 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). Abeta 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 Abeta extracted in pure-formic acid. We demonstrated that amino-truncated Abeta species represented more than 60% of all Abeta species, not only in full blown AD, but also, and more interestingly, at the earliest stage of Alzheimer pathology. At this stage, Abeta oligomers were exclusively made of Abeta-42 species, most of them being amino-truncated. Thus, our results strongly suggest that amino-truncated Abeta-42 species are instrumental in the amyloidosis process. In conclusion, a vaccine specifically targeting these pathological amino-truncated species of Abeta-42 are likely to be doubly beneficial, by inducing the production of specific antibodies against pathological Abeta products that are, in addition, involved in the early and basic mechanisms of amyloidosis in humans.