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

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Amyloid beta (Aβ) 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. Aβ 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 Aβ that accumulates in Alzheimer brain. All these species with their different N-and with or without modifications have different aggregation properties. Aβ requires an aggregated state to be pathogenic and the exact aggregation state is a major determinant of the cellular effects of Aβ: smaller oligomeric aggregates are more neurotoxic, whereas large fibrillar aggregates are generally more associated with a glial response. It is therefore increasingly clear that Aβ 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 Aβ 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 Aβ species: inhibition of the formation of Aβ, inhibition of aggregation and stimulation of its degradation or clearance.
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Keywords: Alzheimer's disease; aggregation; amino acid modification; proteolysis; secretase; therapy; β-amyloid

Document Type: Research Article

Affiliations: Neurogenetics laboratory, Academic Medical Center, P.O.Box 22660, 1100 Amsterdam, The Netherlands.

Publication date: 2010-01-01

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