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.

The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically.

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and

Ceruloplasmin is an iron-export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro-oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD.

In studies of Alzheimer's disease pathogenesis there is an increasing focus on mechanisms of intracellular amyloid-␤ (A␤) generation and toxicity. Here we investigated the inhibitory potential of the 42 amino acid A␤ peptide (A␤ 1-42 ) on activity of electron transport chain enzyme complexes in human mitochondria. We found that synthetic A␤ 1-42 specifically inhibited the terminal complex cytochrome c oxidase (COX) in a dose-dependent manner that was dependent on the presence of Cu 2ϩ and specific "aging" of the A␤ 1-42 solution. Maximal COX inhibition occurred when using A␤ 1-42 solutions aged for 3-6 h at 30°C. The level of A␤ 1-42 -mediated COX inhibition increased with aging time up to ϳ6 h and then declined progressively with continued aging to 48 h. Photo-induced cross-linking of unmodified proteins followed by SDS-PAGE analysis revealed dimeric A␤ as the only A␤ species to provide significant temporal correlation with the observed COX inhibition. Analysis of brain and liver from an Alzheimer's model mouse (Tg2576) revealed abundant A␤ immunoreactivity within the brain mitochondria fraction. Our data indicate that endogenous A␤ is associated with brain mitochondria and that A␤ 1-42 , possibly in its dimeric conformation, is a potent inhibitor of COX, but only when in the presence of Cu 2ϩ . We conclude that Cu 2ϩ -dependent A␤-mediated inhibition of COX may be an important contributor to the neurodegeneration process in Alzheimer's disease.

J. Neurochem. (2012) 120 (Suppl. 1), 149–166. Abstract The biggest risk factor for Alzheimer’s disease is the process of ageing, but the mechanisms that lead to the manifestation of the disease remain to be elucidated. Why age triggers the disease is unclear but an emerging theme is the inability for a cell to efficiently maintain many key processes such as energy production, repair, and regenerative mechanisms. Metal ions are essential to the metabolic function of every cell. This review will explore the role and reported changes in metal ions in Alzheimer disease, particularly the brain, blood and cerebral spinal fluid, emphasizing how iron, copper and zinc may be involved through the interactions with amyloid precursor protein, the proteolytically cleaved peptide amyloid‐beta (Aβ), and other related metalloproteins. Finally, we explore the monomeric makeup of possible Aβ dimers, what a dimeric Aβ species from Alzheimer’s disease brain tissue is likely to be composed of, and discuss how metals may influence Aβ production and toxicity via a copper catalyzed dityrosine cross‐link.

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Background:Cu II (atsm) [(diacetylbis(N(4)-methylthiosemicarbazonato) copper(II)] was orally administrated to transgenic SOD1 G93A mice. Results: Treatment significantly prolonged lifespan with preservation of motor neurons. Reduced protein oxidation, attenuated astrocyte, and microglial activation also resulted from treatment. Conclusion:Cu II (atsm) is neuroprotective in this model even when treatment begins after the onset of disease symptoms. Significance: The drug has therapeutic potential for amyotrophic lateral sclerosis.