Abstract
Amyloid beta (Aβ) is the main component of one of the major pathological hallmarks of Alzheimers 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.
Keywords: Alzheimer's disease, β-amyloid, aggregation, secretase, amino acid modification, proteolysis, therapy
Current Medicinal Chemistry
Title: From Alpha to Omega with Aβ: Targeting the Multiple Molecular Appearances of the Pathogenic Peptide in Alzheimers Disease
Volume: 17 Issue: 3
Author(s): L. De Kimpe and W. Scheper
Affiliation:
Keywords: Alzheimer's disease, β-amyloid, aggregation, secretase, amino acid modification, proteolysis, therapy
Abstract: Amyloid beta (Aβ) is the main component of one of the major pathological hallmarks of Alzheimers 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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Cite this article as:
De Kimpe L. and Scheper W., From Alpha to Omega with Aβ: Targeting the Multiple Molecular Appearances of the Pathogenic Peptide in Alzheimers Disease, Current Medicinal Chemistry 2010; 17 (3) . https://dx.doi.org/10.2174/092986710790149765
DOI https://dx.doi.org/10.2174/092986710790149765 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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