From Alpha to Omega with Aβ: Targeting the Multiple Molecular Appearances of the Pathogenic Peptide in Alzheimer's Disease

Amyloid beta ( A) is the main component of one of the major pathological hallmarks of Alzheimer's disease and is generally considered as one of the earliest factors that induce the pathogenic cascade. A is produced from a larger precursor protein through proteolytic cleavage by secretase activities, which results in fragments that differ in size depending on the cleavage site used to create the C-terminus. In addition, heterogeneity at the N-terminus is created by proteases/peptidases. Moreover, various amino acid modifications further enhance the heterogeneity of A that accumulates in Alzheimer brain. All these species with their different N-and with or without modifications have different aggregation properties. A requires an aggregated state to be pathogenic and the exact aggregation state is a major determinant of the cellular effects of A : smaller oligomeric aggregates are more neurotoxic, whereas large fibrillar aggregates are generally more associated with a glial response. It is therefore increasingly clear that A is not a single entity, but a peptide with multiple molecular appearances. In this review we will discuss the mechanisms leading to the generation of the different A species and their involvement in Alzheimer pathogenesis. This will be discussed in the framework of therapeutic approaches that target one of the steps in the biogenesis of toxic A species: inhibition of the formation of A, inhibition of aggregation and stimulation of its degradation or clearance.