Biometals and Their Therapeutic Implications in Alzheimer's Disease

Ayton, Scott; Lei, Peng; Bush, Ashley I.

doi:10.1007/s13311-014-0312-z

Cited by 112 publications

(103 citation statements)

References 226 publications

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“…In AD pathology, metals such as iron, copper, and zinc interact with Aβ [28]. APP translation is promoted by iron [29,30], and we observed increased APP levels in Aβ-injected mice (Figs.…”

Section: Increased Hippocampal Iron Induced By Aβmentioning

confidence: 65%

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Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Lei

Tuo

et al. 2015

Neurotherapeutics

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The amyloid cascade hypothesis of Alzheimer's disease (AD) positions tau protein as a downstream mediator of β-amyloid (Aβ) toxicity This is largely based on genetic cross breeding, which showed that tau ablation in young (3-7-month-old) transgenic mice overexpressing mutant amyloid precursor protein (APP) abolished the phenotype of the APP AD model. This evidence is complicated by the uncertain impact of overexpressing mutant APP, rather than Aβ alone, and for potential interactions between tau and overexpressed APP. Cortical iron elevation is also implicated in AD, and tau promotes iron export by trafficking APP to the neuronal surface. Here, we utilized an alternative model of Aβ toxicity by directly injecting Aβ oligomers into the hippocampus of young and old wild-type and tau knockout mice. We found that ablation of tau protected against Aβ-induced cognitive impairment, hippocampal neuron loss, and iron accumulation. Despite injected human Aβ being eliminated after 5 weeks, enduring changes, including increased APP levels, tau reduction, tau phosphorylation, and iron accumulation, were observed. While the results from our study support the amyloid cascade hypothesis, they also suggest that downstream effectors of Aβ, which propagate toxicity after Aβ has been cleared, may be tractable therapeutic targets.

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Section: Increased Hippocampal Iron Induced By Aβmentioning

confidence: 65%

“…We found that one of the persistent effects of Aβ intoxication was increased local iron levels (Fig. 8), which is also pathology of AD [28,39]. Lowering brain iron has been shown to reduce memory deficits and neuronal loss in AD animal models and in a clinical trial [11,14,[40][41][42][43].…”

Section: Discussionmentioning

confidence: 79%

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Lei

Tuo

et al. 2015

Neurotherapeutics

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“…52,102,103,104 Despite the neurotoxicity in mice that our studies have elaborated, clinical lithium pharmacotherapy has predominantly neurotrophic benefits in the treatment of bipolar disorder. It is an intriguing hypothesis to consider that these benefits might be related to the correction of iron deficiency in certain brain regions.…”

Section: Discussionmentioning

confidence: 98%

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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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 T 2 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, tauand 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.

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“…While the relation of copper and zinc to AD and the APP protein has proven quite solid, evidence supporting a link between iron and AD has taken much longer to emerge [69]. Elevated brain iron has been reported in patients with AD [70,71].…”

Section: Iron In Alzheimer's Diseasementioning

confidence: 99%

Iron, Aging, and Neurodegeneration

Angelova

Brown

2015

Metals

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Abstract:Iron is a trace element of considerable interest to both chemistry and biology. In a biological context its chemistry is vital to the roles it performs. However, that same chemistry can contribute to a more deleterious role in a variety of diseases. The brain is a very sensitive organ due to the irreplaceable nature of neurons. In this regard regulation of brain iron chemistry is essential to maintaining neuronal viability. During the course of normal aging, the brain changes the way it deals with iron and this can contribute to its susceptibility to disease. Additionally, many of the known neurodegenerative diseases have been shown to be influenced by changes in brain iron. This review examines the role of iron in the brain and neurodegenerative diseases and the potential role of changes in brain iron caused by aging.

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Biometals and Their Therapeutic Implications in Alzheimer's Disease

Cited by 112 publications

References 226 publications

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Iron, Aging, and Neurodegeneration

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