Molecular mechanisms in Alzheimer's disease and related potential treatments such as structural target convergence of antibodies and simple organic molecules

Abstract

The amyloid cascade is the most frequently accepted hypothesis of Alzheimer's Disease (AD). According to this hypothesis, the formation of plaques precedes the appearance of fibrillary tangles. Therapeutic agents able to inhibit the formation of plaques are therefore considered as potential disease-modifying treatments (DMT) that could prevent or limit the progression of AD. Plaques are deposits formed by aggregates of amyloid-β (Aβ)-peptides. These peptides are metabolites of amyloid precursor protein (APP) first mediated by two enzymes: β-secretase 1 (BACE1) and γ-secretase. Molecular identification of these two enzymes has stimulated the development of their inhibitors. The clinical testing of these two classes of molecules has not been successful to date. The oligomerization of Aβ-peptides into plaques is now targeted by immunological approaches such as antibodies and vaccines. Structural consideration of the Aβ-peptide sequence led to the launch of the antibody Aducanumab. Several other antibodies are in late clinical phases. Progress in the understanding of the effects of N-truncated Aβ-peptides such as pE3-42, formed by the action of recently well characterized enzymes (aminopeptidase A, dipeptidylpeptidase-4 and glutaminyl cyclase) suggests that oligomerization can be limited either by enzyme inhibitors or antibody approaches. This strategy associating two structurally interconnected mechanisms is focused in this review.

Keywords: Alzheimer's disease; Aβ-peptides; Disease-modifying therapy; Enzyme inhibitors; N-truncation.