![]() ![]() ![]() However, the role of iron in the aggregation of Aβ has been questioned because of the biophysical evidence that there is no high affinity interaction between the two ( 16). Accordingly, we have shown that ferritin heavy chain can reduce oxidative damage in our model system remarkably, ferritin is able to exert these beneficial effects despite a concomitant increase, sometimes more than 2-fold, in the accumulation of Aβ in the brains of flies ( 8). Iron accumulates in the brain with age ( 10, 11) and may have a role in the oxidative damage that is observed in AD ( 12, – 15), possibly by catalyzing the Fenton conversion of hydrogen peroxide to the highly toxic hydroxyl radical ( 8). Notably, we found that overexpression of the heavy chain of the iron-binding protein ferritin affords a complete rescue of the locomotor deficits that result from Aβ expression ( 8). Indeed, we and others have shown that both genetic and pharmacological manipulation of iron metabolism in the fly ( 8) and mouse ( 9) brain can modify Aβ toxicity. Using this system, we performed an unbiased genetic modifier screen that highlighted the importance of iron metabolism as a cofactor in mediating the Aβ toxicity ( 8). The consequent phenotypes correlate well with the propensity of a range of Aβ variants to form soluble aggregates ( 7). ![]() We have generated a model system in which Aβ peptides are secreted from neurons in the brain of Drosophila melanogaster ( 6). However, the mature amyloid fibrils that constitute these plaques are not thought to be the prime cytotoxic agent rather there is strong evidence both in vitro and in vivo that the most toxic Aβ aggregates are small, soluble species that precede, but may also accompany, the appearance of mature fibrils ( 5). In both sporadic and familial AD, however, it is the aggregation-prone Aβ peptide that comprises the amyloid plaques that are seen in the brain of individuals with AD ( 4). In some families, mutations in the APP gene result in amino acid substitutions within the Aβ peptide a particular example of this is the Arctic mutation (E22G) that is linked to early onset autosomal dominant AD ( 3). In the case of Aβ 1–40, the peptide is 40 amino acids long and does not contain the final two hydrophobic residues that are present in the more aggregation-prone Aβ 1–42. Aβ is generated by the proteolytic processing of the amyloid precursor protein, and the behaviors of the resulting peptide isoforms, largely Aβ 1–40 and Aβ 1–42, are determined in large part by differences in their C-terminal residues. It is widely believed that an important initiating factor is the accumulation of the amyloid β peptide (Aβ) within the brain ( 1, 2). These data support the hypothesis that iron delays the formation of well ordered aggregates of Aβ and so promotes its toxicity in Alzheimer disease.ĪD 3 remains the most common cause of dementia in the elderly however, our incomplete understanding of its pathogenesis hinders therapeutic progress. Finally, using mammalian cell culture systems, we have shown that iron specifically enhances Aβ toxicity but only if the metal is present throughout the aggregation process. We find that iron slows the progression of the Aβ peptide from an unstructured conformation to the ordered cross-β fibrils that are characteristic of amyloid. To understand the pathogenic mechanisms, we have used biophysical techniques to see how iron affects Aβ aggregation. We confirm that chelation of iron protects the fly from the harmful effects of Aβ. In this study, we have used an iron-selective chelating compound and RNAi-mediated knockdown of endogenous ferritin to further manipulate iron in the brain. These data point to an important pathogenic role for iron in Alzheimer disease. We have previously shown that overexpressing subunits of the iron-binding protein ferritin can rescue the toxicity of the amyloid β (Aβ) peptide in our Drosophila model system. ![]()
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