β-Amyloid Fibrils in Alzheimer Disease Are Not Inert When Bound to Copper Ions but Can Degrade Hydrogen Peroxide and Generate Reactive Oxygen Species

Abstract

Background: Metal-associated ␤-amyloid (A␤) aggregates are implicated in the pathogenesis of Alzheimer disease. Results: Copper bound A␤(1-42) aggregates, including fibrils, degrade hydrogen peroxide, forming hydroxyl radicals and carbonyls. Conclusion: Copper-bound A␤ fibrils can retain redox activity. Significance: A␤ fibrils bound to copper are not inert end points and may be a source of oxidative stress in the Alzheimer brain.

Synthesis and Characterization of Hairpin Mimics that Modulate the Early Oligomerization and Fibrillization of Amyloid β‐Peptide

“…Low molecular weight oligomers have been considered for the last decade by several groups as being primarily responsible for the neurodegeneration observed in AD, by inducing physical changes in the cell membrane leading to dysfunction and cell death , , . In addition, fibrils are not inert species because they have been demonstrated to generate damaging redox activity and to promote the nucleation of toxic oligomers . As a consequence, reducing the prevalence of both fibrils and small transient oligomers has become an essential criterion for the evaluation and selection of small therapeutic molecules.…”

Free Superoxide is an Intermediate in the Production of H2O2 by Copper(I)‐Aβ Peptide and O2

“…[21,22] In contrast to the well supported production of H 2 O 2 and HOC,d etection of O 2 C À by nitro blue tetrazolium (NBT) or hydroethidine failed. [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab). [9,14,18,23,24] This seems coherent, because considering the redox potentials at neutral pH the electron reduction from O 2 to H 2 O 2 is ad own-hill reaction (exergonic), in contrast to the endergonic one-electron reduction of O 2 to O 2 C À .C omputational chemistry supported that Cu I -Ab can activate O 2 to form O 2 C À , [25,26] and that no O 2 C À is released during the H 2 O 2 production (O 2 C À was proposed as an intermediate bound to Cu-Ab).…”

Dantrolene, A Treatment for Alzheimer Disease?

“…13-15 Histopathological and genetic evidence form the basis of the amyloid cascade hypothesis, which states that deposition of Aβ is the initiating event that triggers neuronal dysfunction and death. 16-18 Aβ peptides constitute a major part of the neuritic plaques causing neurotoxicity, which are cleaved from APP by β- and γ-secretases. 19 Hitherto, much of the research focus in the AD field has been on Aβ peptide generation and its mechanisms of action.…”

“…20-22 Despite the efforts to characterize the molecular mechanisms underlying Aβ's toxicity, it remains unclear what triggers the accumulation of the peptide and whether such action is the primary cause of AD pathogenesis and cognitive dysfunction. 18,23-26 However, the amyloid cascade hypothesis still dominates the search for AD disease treatments up to now. For example, researchers have tried to reduce Aβ production by developing molecules that inhibit γ-secrease activity, block Aβ aggregation and promote Aβ clearance.…”