Abstract
Central to the pathogenesis of Alzheimer's disease (AD) is the conversion of normal, soluble β-amyloid (sAβ) to oligomeric, fibrillar Aβ. This process of conformational conversion can be influenced by interactions with other proteins that can stabilize the disease-associated state; these proteins have been termed 'pathological chaperones'. In a number of AD models, intervention that block soluble Aβ aggregation, including β-sheet breakers, and compounds that block interactions with pathological chaperones, have been shown to be highly effective. When combined with early pathology detection, these therapeutic strategies hold great promise as effective and relatively toxicity free methods of preventing AD related pathology.
Highlights
Formation of β-amyloid (Aβ) fibrils and deposition of Aβ in the brain parenchyma, or in the brain's vessels, occurs in the setting of increased Aβ peptide concentrations [1,2]
Aβ homologous peptides can spontaneously aggregate and form fibrils in vitro; in vivo this process appears more dependant on Aβ pathological chaperones
Ma et al [37] have demonstrated that a synthetic peptide homologous to this sequence of Aβ can be used as a competitive inhibitor of the binding of full length Aβ to apoE, resulting in reduced fibril formation in vitro and increased survival of cultured neurons
Summary
Formation of β-amyloid (Aβ) fibrils and deposition of Aβ in the brain parenchyma, or in the brain's vessels, occurs in the setting of increased Aβ peptide concentrations [1,2]. Several Aβ homologous peptides have been identified that have amino acid substitutions using residues such as proline and can bind to Aβ oligomers and fibril structures, leading to disruption of the β-sheet conformation [9,10,11,12]. Aβ homologous peptides can spontaneously aggregate and form fibrils in vitro; in vivo this process appears more dependant on Aβ pathological chaperones.
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