The amyloid  peptide is toxic to neurons, and it is believed that this toxicity plays a central role in the progression of Alzheimer's disease. The mechanism of this toxicity is contentious. Here we report that an A peptide with the sulfur atom of Met-35 oxidized to a sulfoxide (Met(O)A) is toxic to neuronal cells, and this toxicity is attenuated by the metal chelator clioquinol and completely rescued by catalase implicating the same toxicity mechanism as reduced A. However, unlike the unoxidized peptide, Met(O)A is unable to penetrate lipid membranes to form ion channel-like structures, and -sheet formation is inhibited, phenomena that are central to some theories for A toxicity. Our results show that, like the unoxidized peptide, Met(O)A will coordinate Cu 2؉ and reduce the oxidation state of the metal and still produce H 2 O 2 . We hypothesize that Met(O)A production contributes to the elevation of soluble A seen in the brain in Alzheimer's disease.Genetic evidence from early onset cases of Alzheimer's disease indicates that metabolism of the -amyloid peptide (A)
The toxicity of the amyloid- peptide (A) is thought to be responsible for the neurodegeneration associated with Alzheimer disease. Generation of hydrogen peroxide has been implicated as a key step in the toxic pathway. A coordinates the redox active metal ion Cu 2؉ to catalytically generate H 2 O 2 . Structural studies on the interaction of A with Cu have suggested that the coordination sphere about the Cu 2؉ resembles the active site of superoxide dismutase 1. To investigate the potential role for such structures in the toxicity of A, two novel A40 peptides, A40(HisMe) and A40(HisMe), have been prepared, in which the histidine residues 6, 13, and 14 have been substituted with modified histidines where either the -or -nitrogen of the imidazole side chain is methylated to prevent the formation of bridging histidine moieties. These modifications did not inhibit the ability of these peptides to form fibrils. However, the modified peptides were four times more effective at generating H 2 O 2 than the native sequence. Despite the ability to generate more H 2 O 2 , these peptides were not neurotoxic. Whereas the modifications to the peptide altered the metal binding properties, they also inhibited the interaction between the peptides and cell surface membranes. This is consistent with the notion that A-membrane interactions are important for neurotoxicity and that inhibiting these interactions has therapeutic potential. Alzheimer disease (AD)1 is characterized by the deposition of amyloid plaques; the major constituent of plaques is the amyloid- peptide (A), which is proteolytically derived from the membrane-bound amyloid precursor protein (1-3). A has been implicated as a causative agent in the progression of AD (4), and evidence is emerging supporting copper, iron, and redox silent zinc in the pathogenesis of AD (reviewed in Refs. 5 and 6). Two of the defining hallmarks of AD are peptide aggregation and the generation of reactive oxygen species, both of which are consequences of A coordinating metal ions (5).The importance of Zn 2ϩ in plaque formation has been emphasized by the finding that age-and female sex-related plaque formation in Tg2576 transgenic mice was greatly reduced upon the genetic ablation of the zinc transporter 3 protein, which is required for zinc transport into synaptic vesicles (7). The plaques represent "metallic sinks" because high concentrations of Cu (400 M), Zn (1 mM), and Fe (1 mM) have been found in amyloid deposits in AD-affected brains (8, 9).Results obtained in both transgenic animals and the clinic utilizing an orally available metal chelator, clioquinol, further highlight the importance of metal ions to AD pathogenesis. In Tg2576 mice, clioquinol treatment markedly decreased A deposition and improved the general health and body weight (10). These results led to a pilot phase II clinical trial in which clioquinol inhibited cognitive decline and decreased plasma A42 levels in patients with moderate to severe AD (11).A possesses histidine residues at positions 6, 13, and ...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.