From alpha to omega with Abeta: targeting the multiple molecular appearances of the pathogenic peptide in Alzheimer's disease.
Amyloid beta (Abeta) 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. Abeta 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 Abeta that accumulates in Alzheimer brain. All these species with their different N-and C termini, with or without modifications have different aggregation properties. Abeta requires an aggregated state to be pathogenic and the exact aggregation state is a major determinant of the cellular effects of Abeta: smaller oligomeric aggregates are more neurotoxic, whereas large fibrillar aggregates are generally more associated with a glial response. It is therefore increasingly clear that Abeta 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 Abeta 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 Abeta species: inhibition of the formation of Abeta, inhibition of aggregation and stimulation of its degradation or clearance.
De Kimpe
L
L
Neurogenetics laboratory, Academic Medical Center, PAmsterdam, The Netherlands.
Scheper
W
W
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008969:Molecular Sequence Data; D058225:Plaque, Amyloid / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins