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The proteolytic cleavage of β-amyloid precursor protein (APP) to form the amyloid beta (Aβ) peptide is related to the pathogenesis of Alzheimer's disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aβ formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aβ-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.

The proteolytic cleavage of β-amyloid precursor protein (APP) to form the amyloid beta (Aβ) peptide is related to the pathogenesis of Alzheimer's disease (AD) because APP mutations that influence this processing either induce familial AD or mitigate the risk of AD. Yet Aβ formation itself may not be pathogenic. APP promotes neuronal iron efflux by stabilizing the cell-surface presentation of ferroportin, the only iron export channel of cells. Mislocalization of APP can promote iron retention, thus we hypothesized that changes in endocytotic trafficking associated with altered APP processing could contribute to the neuronal iron elevation and oxidative burden that feature in AD pathology. Here, we demonstrate, using genetic and pharmacological approaches, that endocytotic amyloidogenic processing of APP impairs iron export by destabilizing ferroportin on the cell surface. Conversely, preferential non-amyloidogenic processing of APP at the cell surface promotes ferroportin stabilization to decrease intraneuronal iron. A new Aβ-independent hypothesis emerges where the amyloidogenic processing of APP, combined with age-dependent iron elevation in the tissue, increases pro-oxidant iron burden in AD.

Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tau- and amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer’s disease), and may explain lithium-associated motor symptoms in susceptible patients.

The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.