Iron, Copper, and Zinc Concentration in Aβ Plaques in the APP/PS1 Mouse Model of Alzheimer’s Disease Correlates with Metal Levels in the Surrounding Neuropil

James, Simon; Churches, Quentin I.; Jonge, Martin D. de; Birchall, Ian; Streltsov, V.A.; McColl, Gawain; Adlard, Paul A.; Hare, Dominic J.

doi:10.1021/acschemneuro.6b00362

Cited by 110 publications

(81 citation statements)

References 50 publications

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“…The copper in plaques of AD transgenic mice, quantified by XRF microscopy, appears consistent with that of the surrounding neuropil after accounting for local tissue density (James et al, 2017). Leskovjan et al (2009) argued that failure to observe increased levels of Cu in plaques within APP transgenic mouse models of AD is due to inadequate time for plaques to “sink” this metal within their shorter lifespan and that this is consistent with the absence of neurodegeneration in those models (Bourassa and Miller, 2012).…”

Section: Is There Mislocalized Copper In the Ad Brain?mentioning

confidence: 85%

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

Drew

2017

Front. Neurosci.

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The “therapeutic chelation” approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with the premise that small molecules can be designed to prevent transition metal-induced amyloid deposition and oxidative stress within the AD brain. Over more than 20 years, countless in vitro studies have been devoted to characterizing metal binding, its effect on Aβ aggregation, ROS production, and in vitro toxicity. Despite a lack of evidence for any clinical benefit, the conjecture that therapeutic chelation is an effective approach for treating AD remains widespread. Here, the author plays the devil's advocate, questioning the experimental evidence, the dogma, and the value of therapeutic chelation, with a major focus on copper ions.

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Section: Is There Mislocalized Copper In the Ad Brain?mentioning

confidence: 85%

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

Drew

2017

Front. Neurosci.

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“…The trigger of the pathologic Aβ aggregation in AD is unknown (Musiek and Holtzman, 2015); however, in animal models of AD, the conversion of a monomeric Aβ into fibrillar aggregates, through neurotoxic oligomers, is triggered by chemically and structurally modified Aβ species (Meyer-Luehmann et al, 2006; Prusiner, 2012; Jucker and Walker, 2013). Amyloid plaques are abnormally rich in Fe, Cu, and Zn ions (Cummings, 2004), and data from animal models suggest that the formation of amyloid plaques is zinc dependent (Friedlich et al, 2004; Frederickson et al, 2005; DeGrado et al, 2016; James et al, 2017). It has been assumed that zinc ions promote Aβ aggregation via a population shift of polymorphic states (Miller et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition

Barykin

Petrushanko

Kozin

et al. 2018

Front. Mol. Neurosci.

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The triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aβ, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aβ are neutralized by its phosphorylation.

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“…The role of Zn in the onset of pathologies in TBI and dementia has been hypothesised for some time, 9 in part due to the effect of Zn on the aggregation, oligomerisation and deposition of pathological proteins. 31 It is also noteworthy that in Alzheimer's disease decreased cellular Zn at the cellular level may contribute to neuropathology via Zn sequestration in senile plaques, 32 reducing the pool of readily-available synaptic Zn. 33 Synaptic Zn is vital for normal memory function and cognition.…”

Section: Discussionmentioning

confidence: 99%

Trehalose elevates brain zinc levels following controlled cortical impact in a mouse model of traumatic brain injury

et al. 2018

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a Zinc (Zn) deficiency is a clinical consequence of brain injury that can result in neuropathological outcomes that are exacerbated with age. Here, we present laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging data showing modulation of brain Zn levels by the disaccharide trehalose in aged mice following a controlled cortical impact model of traumatic brain injury. In this proofof-concept study, trehalose induced an increase in brain zinc levels, providing important preliminary data for larger studies using this simple carbohydrate as a modulator of this essential micronutrient in traumatic brain injury. Our results may have further implications for the treatment of a variety of neurodegenerative diseases and other disorders of the nervous system. Significance to metallomicsTraumatic brain injury can result in both acute and chronic neurological dysfunction. Zinc is an essential micronutrient involved in a multitude of critical neurological processes, including the biological response to brain injury. In this research manuscript we describe the results of a proof-of-concept study that treated mice with the disaccharide trehalose, delivered orally for 28 days following a controlled cortical impact. Trehalose induced an increase in brain zinc levels, providing important preliminary data for larger studies using this simple carbohydrate as a modulator of this essential micronutrient, which may have implications for the treatment of a variety of neurodegenerative diseases and other disorders of the nervous system.

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Iron, Copper, and Zinc Concentration in Aβ Plaques in the APP/PS1 Mouse Model of Alzheimer’s Disease Correlates with Metal Levels in the Surrounding Neuropil

Cited by 110 publications

References 50 publications

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition

Trehalose elevates brain zinc levels following controlled cortical impact in a mouse model of traumatic brain injury

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