Basic Science and Pathogenesis.

Background: Amyloid filaments formation is a complex kinetic and thermodynamic process. The dependence of peptide polymerization on peptide-peptide interactions to form a β-pleated sheet fibrils and the stimulatory influence of other proteins on the reaction suggest that amyloid formation may be subject to modulation METHOD: In vitro formation of β-amyloid was induced by incubation of an aqueous solution of AβP (10 mg/ml) for 7 days at 37°C. The extent of β-amyloid formation and disaggregation were monitored using a panel of well characterized mAbs raised against soluble AβP fragments. The aggregation of Aβ was measured by the ThT binding assay, in which the fluorescence intensity reflects the degree of β-amyloid fibrillar aggregation.

Result: The epitopes of the anti -aggregated antibodies were localized employing a library of filamentous phage displaying random combinatorial hexapeptides. Among 44 phages, the consensus sequence EFRH was carried by 40 clones. The EFRH (3-6) of AβP located at the N-terminal is exposed for antibody binding in both forms, either in solution or an aggregate, suggesting that he is involved in the aggregation process and acts as a regulatory site controlling both the prevention and the disaggregation process.

Conclusion: Our pioneering data were recently confirmed by successful Aducanumab (3-7) and Lecanemab (1-16) antibodies that recognize the N terminus of Aβ and selectivity bind to aggregated Aβ species. Naturally occurring anti-AβP antibodies have been found in human CSF and in the plasma of healthy individuals, from where Aducanumab was derived, but were significantly lower in Alzheimer's disease patients.