Amyloid β Peptides Do Not Form Peptide-derived Free Radicals Spontaneously, but Can Enhance Metal-catalyzed Oxidation of Hydroxylamines to Nitroxides

Abstract

As the leading cause of dementia, Alzheimer's disease (AD) 1 is characterized by a loss of memory and neurons. These characteristics have been associated with brain lesions known as neurofibrillary tangles composed of Tau protein and amyloid plaques, which consist of amyloid ␤ (A␤) peptide. In a small number of families, mutations in the genes for the amyloid peptide precursor (APP, chromosome 21) to A␤ peptide for presenilin-1 (PSEN-1, chromosome 14), presenilin-2 (PSEN-2, chromosome 1) and for an anonymous gene on chromosome 12 have been associated with AD. In contrast, Saunders and colleagues (1) discovered that a significant percentage of patients inheriting one or more of the epsilon-4 alleles of apolipoprotein-E (APOE4, chromosome 19) were at risk of acquiring AD at an earlier age than their counterparts expressing the more common epsilon-3 allele of APOE. The observation that AD patients with mutant genes for APP, PSEN-1, or PSEN-2 have higher levels of A␤ peptide than non-diseased controls (2, 3) argues that A␤ peptide may cause AD. Further supporting this idea is the observation that APOE4 patients with AD display more amyloid plaques than those with APOE3 (4). Based on neuropathological, genetic, and biochemical associations, the presence of amyloid ␤ peptide is a key component of AD.A crucial link between A␤ peptide and AD was provided by Yankner and colleagues (5), who showed that fibrillar aggregates of A␤ peptide were toxic to neurons. This seminal observation inspired a global quest to define the mechanism by which fibrillar A␤ peptide mediated neurotoxicity. One of the mechanisms proposed suggests that neurons exposed to A␤ peptide suffer severe oxidative stress that may lead to their death. Clear evidence of oxidative stress in Alzheimer's disease has been provided by Smith et al. (6), who found that neurons of AD patients contained nitrotyrosine modifications of proteins, which were not detected in age-matched control brains. Increased levels of lipid peroxides (7), reactive aldehydes such as hydroxynonenal (8), and oxidized DNA (9) have also been reported in AD brains, providing additional evidence of an oxidative stress component in the disease.The exact nature of the radical species generated in Alzheimer's diseased brains is unknown. In one line of investigation, Behl et al. (10) demonstrated that cells exposed to fibrillar A␤ peptide responded by releasing hydrogen peroxide and dying, a process that could be inhibited by the application of catalase to degrade the released peroxide. Subsequent reports have demonstrated cellular release of superoxide (11) and nitric oxide (12) in response to A␤ peptide treatment. The effect of these radicals may be potentiated since A␤ peptides also appear to inhibit the cellular redox mechanisms that normally protect cells from oxidative stress (13).In a provocative hypothesis, Hensley et al. (14) suggest that the A␤ peptide itself spontaneously generates free radicals that can damage cells. By mixing the spin trap N-tert-butyl-␣-phenylnitrone (PBN) with ...

New Class of Inhibitors of Amyloid-β Fibril Formation

“…all of which are associated with the autoxidation of these compounds and are thought to mediate their cytotoxicity (50,51). In addition, A␤-peptides have been shown to enhance the oxidation of hydroxylamine derivatives without the formation of peptide-derived free radicals (52). The results presented in this paper suggest that autoxidation products of apomorphine and its derivatives could exacerbate A␤ toxicity by stabilizing toxic A␤ protofibrillar intermediates.…”

The chemistry and biology of nitroxide compounds

“…Tempol also protected mice from developing Parkinsonian symptoms induced by administration of 6-OHDA. A study of several toxic brain peptides associated with Alzheimer's revealed that they were capable of oxidizing the nitroxide Tempone [86] although the significance of this finding is difficult to ascertain, however, as they do not spontaneously produce free radicals and the contribution of ROS to the development of Alzheimer's is not well characterized [86].…”

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

“…The three histidine residues of amyloid-b at position 6, 13, and 14 and one tyrosine residue at position 10, all located in the hydrophilic N-terminal part of the peptide [43,44], behave as iron binding sites. The iron bound to these sites has been shown to generate H 2 O 2 by the Fenton reaction [45][46][47]. Not only production of ROS but also binding of iron to these residues induces amyloid-b aggregation.…”