Copper in Alzheimer’s disease: Implications in amyloid aggregation and neurotoxicity

Abstract

The relationship of copper dyshomeostasis with neurodegenerative diseases has become evident in the last years. Because of the major role that this metal ion plays in biological processes, most of which being located in the brain, it is not surprising that changes in its distribution are closely related with the advent of neurodegenerative disorders such as Alzheimer’s disease (AD). An increasing number of works have dealt with this subject in the last years, and opened an intense debate in some points while raising new questions that still remain unanswered. This revision work puts together and discusses the latest findings and insights on how copper ions are involved in AD progression, including its interaction with Aβ and its consequently induced aggregation.

Histidine‐Rich Oligopeptides To Lessen Copper‐Mediated Amyloid‐β Toxicity

“…The conditionalaffinity constants of the three peptides have been determined by intrinsic fluorescence measurements, and are two orderso fm agnitude highert han that previously reportedf or Ab . Competitive binding studies based on fluorescencem easurements using either Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) or bacterial inclusionb odies of Ab42-GFP have confirmed their efficient ability to displace Ab-bound Cu II ions in an irreversible fashion. ThT emission studies have suggested that copper-induced oligomer aggregation of Ab is indeed inhibited in the presence of the peptides, and on adding the peptides to Cu-induced fibrils am odulation of such fibrillation occurred.…”

“…As shown above, the three peptides exhibit Cu 2+ ‐binding affinities that are up to two orders of magnitude higher than that displayed by Aβ(1‐40). To confirm their higher proficiency to “capture” copper(II) ions, competitive binding experiments were performed using the non‐aggregating amyloid fragment Aβ(1‐16) ( K cond =1–2×10 7 m −1 ), following the intrinsic fluorescence of the tyrosine residue Tyr10 of the protein and the emission of a fluorescent tripeptide. For these studies, HK C H was preferred because its emission at 410 nm would not interfere with that of Aβ(1‐16) (emission of tyrosine at 305 nm); the excitation wavelength of HK c H is far enough from that of Aβ(1‐16), in contrast to that for HWH (λ exc =275, 300, and 280 nm for tyrosine, the coumarin group of HK C H , and tryptophan, respectively).…”

“…It shoulda lso be notedt hat peptide-to-copper ratios of 1:2a nd 2:1d id not showa ny shift of the d-d band (i.e.,f rom that observed for the 1:1c omplex), corroborating that solelyt he 1:1s peciesisf ormed. 1 Ha nd 13 CNMR studies:T he paramagnetism of copper(II) was used to furtheri nvestigate its interaction with the tripeptides, taking advantage of the severe broadening of the NMR signals upon copperb inding. [33] The 1 Ha nd 13 CNMR spectra for HWH, HK C H,a nd HAH in the presence of 0.01 equivofc opper(II) are shown in the Supporting Information (Figures S5-S10).…”

“…Competitiveb inding studies between the tripeptides and amyloidp roteins [Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) and Ab(1-42)]:A so utlined above,t he tripeptides HWH, HK C H,a nd HAH were selected with the idea of using them as potential binding compounds to competew ith amyloid-b fragments for copper.A ss hown above,t he three peptides exhibit Cu 2 + -binding affinitiest hat are up to two orders of magnitude highert han that displayed by Ab .T oc onfirmt heir higherp roficiency to "capture" copper(II) ions, competitive binding experiments were performed using the non-aggregating amyloid fragment Ab(1-16) (K cond = 1-2 10 7 m À1 ), [1] following the intrinsic fluorescence of the tyrosine residue Tyr10 of the protein and the emissiono f af luorescent tripeptide. For these studies, HK C H was preferred because its emission at 410 nm would not interferew ith that of Ab(1-16) (emission of tyrosine at 305 nm);t he excitation wavelength of HK c H is far enough from that of Ab (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), in contrastt ot hat for HWH (l exc = 275, 300, and2 80 nm for tyrosine, the coumarin group of HK C H,a nd tryptophan, respectively).…”

“…Recent years have witnessed increasing evidence on the relationship betweencopperd yshomeostasis, amongo ther metal ions such as iron and zinc, and the advent of neurodegenerative disorders such as Alzheimer's disease (AD). [1,2] Copper can bind to amyloid beta-protein (Ab)a nd modulate its aggregation mechanism,a nd indeed Ab aggregates represent one of the hallmarks of AD. [3] The binding of copperi ons to the protein promotes the generation of soluble oligomerics pecies, which are believed to be the most toxic form of Ab.…”