The metal theory of Alzheimer's disease.

Brain homeostasis of transition metals is severely perturbed in Alzheimer's disease (AD), with extracellular pooling of zinc and copper in amyloid, and intraneuronal accumulation of iron. Rapidly accumulating evidence indicates that these perturbances themselves may contribute significantly to the cognitive loss and neurodegeneration, even in the absence of AD proteopathy. There is now strong evidence that each of the major protein participants in AD pathology has physiologically important interactions with transition metals: AβPP is the neuronal iron export ferroxidase with a major interaction with ferroportin, presenilins are needed for the import of ≈ 50% of cellular copper and zinc, and tau promotes the export of neuronal iron by facilitating the trafficking of AβPP to the surface. Therefore, amyloid and tau pathology arise in a milieu of constitutively high metal flux, and the major components of AD pathology may contribute to the disease by failing in their metal transport roles.