amyloid-beta-peptides and formic-acid

Neuropathological, epidemiological and experimental data indicate a potential interrelationship between Alzheimer's disease and prion diseases. Proteolytic processing of amyloid precursor protein (APP) by beta-secretase was recently suggested to be controlled by prion protein expression. Here, we characterized the prion infection of Tg2576 mice, which overexpress the human APP(Swe) protein. Prion infection of Tg2576-mice led to an early death of the animals, which was preceded by a relatively short symptomatic stage. However, disease-associated gliosis and deposition of misfolded prion protein PrP(Sc) were identical in infected Tg2576-mice and non-transgenic littermate controls. To analyze the effect of prion infection on APP processing and generation of beta-amyloid we determined cortical levels of SDS- and formic acid (FA)-extractable forms of beta-amyloid (1-40) and (1-42) by ELISA. Formic acid-extractable Abeta (1-42) levels were 10-fold higher in infected versus uninfected Tg2576 mice whereas other forms of Abeta were essentially unaffected by the prion infection. Hence, the experimental model demonstrates that a prion infection of the CNS promotes selectively formation of FA-extractable Abeta(1-42) in Tg2576 mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Formates; Gliosis; Humans; Mice; Mice, Transgenic; Nerve Degeneration; Neurochemistry; Peptide Fragments; Plaque, Amyloid; Prion Diseases; Prions; PrPSc Proteins; Scrapie; Survival Rate; Up-Regulation

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.

Topics: Alzheimer Disease; Alzheimer Vaccines; Amyloid beta-Peptides; Blotting, Western; Brain Chemistry; Disease Progression; Electrophoresis, Gel, Two-Dimensional; Formates; Humans; Peptide Fragments; Reference Values; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization