Summary Alzheimer’s Disease (AD) is complicated by pro-oxidant intraneuronal Fe2+ elevation as well as extracellular Zn2+ accumulation within amyloid plaque. We found that the AD β-amyloid protein precursor (APP) possesses ferroxidase activity mediated by a conserved H-ferritin-like active site, which is inhibited specifically by Zn2+. Like ceruloplasmin, APP catalytically oxidizes Fe2+, loads Fe3+ into transferrin, and has a major interaction with ferroportin in HEK293T cells (that lack ceruloplasmin) and in human cortical tissue. Ablation of APP in HEK293T cells and primary neurons induces marked iron retention, whereas increasing APP695 promotes iron export. Unlike normal mice, APP−/− mice are vulnerable to dietary iron exposure, which causes Fe2+ accumulation and oxidative stress in cortical neurons. Paralleling iron accumulation, APP ferroxidase activity in AD post-mortem neocortex is inhibited by endogenous Zn2+, which we demonstrate can originate from Zn2+-laden amyloid aggregates and correlates with Aβ burden. Abnormal exchange of cortical zinc may link amyloid pathology with neuronal iron accumulation in AD.

Amelyoid-␤ peptide (A␤) is a major causative agent responsible for Alzheimer's disease (AD). A␤ contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl2 (L ‫؍‬ 1,10-phenanthroline derivatives) complexes were examined and shown to bind to A␤, inhibit neurotoxicity and rescue A␤-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to A␤ altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of A␤. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for A␤ onto the platinum complexes. The potent effect of the L-PtCl 2 complexes identifies this class of compounds as therapeutic agents for AD.

The Amyloid peptide (A ) of Alzheimer's diseases (AD) is closely linked to the progressive cognitive decline associated with the disease. Cu 2+ ions can induce the de noVo aggregation of the A peptide into non-amyloidogenic aggregates and the production of a toxic species. The mechanism by which Cu 2+ mediates the change from amyloid material toward Cu 2+ induced aggregates is poorly defined. Here we demonstrate that the aggregation state of A 1-42 at neutral pH is governed by the Cu 2+ :peptide molar ratio. By probing amyloid content and total aggregation, we observed a distinct Cu 2+ switching effect centered at equimolar Cu 2+ :peptide ratios. At sub-equimolar Cu 2+ :peptide molar ratios, A 1-42 forms thioflavin-T reactive amyloid; conversely, at supra-equimolar Cu 2+ :peptide molar ratios, A 1-42 forms both small spherical oligomers approximately 10-20 nm in size and large amorphous aggregates. We demonstrate that these insoluble aggregates form spontaneously via a soluble species without the presence of an observable lag phase. In seeding experiments, the Cu 2+ induced aggregates were unable to influence fibril formation or convert into fibrillar material. Aged Cu 2+ induced aggregates are toxic when compared to A 1-42 aged in the absence of Cu 2+ . Importantly, the formation of dityrosine crosslinked A , by the oxidative modification of the peptide, only occurs at equimolar molar ratios and above. The formation of dityrosine adducts occurs following the initiation of aggregation and hence does not drive the formation of the Cu 2+ induced aggregates. These results define the role Cu 2+ plays in modulating the aggregation state and toxicity of A 1-42.