Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency

Stoltenberg, Meredin; Bush, Ashley I.; Bach, Georg; Smidt, Kamille; Larsen, Agnete; Rungby, Jørgen; Lund, Sten; Doering, P.; Danscher, Gorm

doi:10.1016/j.neuroscience.2007.09.025

Cited by 110 publications

(87 citation statements)

References 66 publications

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“…Furthermore, post hoc analysis revealed a statistically significant reduction of cognitive decline on two tests (and nearly significant for the MMSE) when analyses were limited to the twenty-nine patients over seventy years old (Brewer 2012). Furthermore, dietary zinc deficiency exacerbated behavioral and histological pathology in an APP mutant mouse (Stoltenberg et al 2007), and zinc supplementation prevented AD pathology in the 3X-Tg mouse model (Corona et al 2010). However, another study found impaired memory performance in zinc supplemented APP mutant mice associated with decreased Ab deposition (Linkous et al 2009).…”

Section: Therapies Aimed At Modulating Zinc Availabilitymentioning

confidence: 95%

“…(3) Zinc stimulates kinases and inhibits protein phosphatases leading to phosphorylation of Tau which promotes the aggregation of Tau in neurofibrillary tangles (NFT) and contributes to a positive feedback loop that further increases postsynaptic calcium influx through NMDARs resulting in neuronal cell death synaptic activity in the APP/PS1 mouse model and direct application of soluble Ab dimers to CA1 neurons increases synaptic activity in wild type mice measured in vivo by calcium imaging (Busche et al 2012). Deficiency of the zinc transporter ZnT3 or the brain specific zinc binding protein metallothionein (MT)3 can prevent deposition of Ab in Swedish mutant APP mice (Lee et al 2002;Manso et al 2012), and senile plaques form preferentially in zinc enriched cortical layers of APP/PS1 mice (Stoltenberg et al 2007). These findings provide further evidence that zinc released from synaptic vesicles could contribute to AD pathology.…”

Section: Risk Of Zinc Deficiency In the Elderlymentioning

confidence: 99%

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Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

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Section: Therapies Aimed At Modulating Zinc Availabilitymentioning

confidence: 95%

Section: Risk Of Zinc Deficiency In the Elderlymentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

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“…Zinc, via the activity of ZNT3, seems pivotal for the formation of amyloid beta in the nervous system [31], a process that occurs in parallel in islets and that may hopefully be interfered with-by the use of metallothioneins or other means-in the future in order to maintain functional beta cells.…”

Section: Perspectivesmentioning

confidence: 99%

Zinc, zinc transporters and diabetes

Rungby

2010

Diabetologia

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The role of zinc in islet function has recently achieved new attention as a consequence of the identification of zinc transporter 8 (ZNT8) in islets, and the association of mutations in the gene for this zinc transporter with glucose intolerance and type 2 diabetes. ZNT8 is also an autoantigen associated with the appearance of type 1 diabetes. A number of experimental models have been employed to suggest how ZNT8 and other zinc transporters regulate beta cell insulin processing and possibly secretion. An additional role for the zinc transporters in regulating alpha cell function has been suggested. In this issue of Diabetologia, Wijesekara and colleagues, using a cell-specific Znt8 (also known as Slc30a8) knockout model, demonstrate that beta cell insulin processing and glucose tolerance is negatively affected after beta cell knock out of Znt8, whereas Znt8 knockout in alpha cells seems to have little effect on glucagon secretion or glucose tolerance. Although we are yet to see the therapeutic potential of these new findings, the area represents a field through which manipulation of islet function may eventually be possible.

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“…In vivo studies reported that Zn 2þ , Cu þ2 , and Fe þ3 are markedly enriched in Aβ plaques (4,5), suggesting that these ions may act as seeding factors. Oligomerization of the Aβ peptides can be rapidly induced in the presence of Zn 2þ ions under physiological conditions (4, 6, 7).…”

mentioning

confidence: 99%

“…Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Solution NMR of Zn 2þ -Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22).…”

mentioning

confidence: 99%

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

Miller

Ma²,

Nussinov³

2010

Proc. Natl. Acad. Sci. U.S.A.

286

288

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Although a key factor in Alzheimer's disease etiology is enrichment of Zn 2þ in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn 2þ -Aβ coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn 2þ can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn 2þ -Aβ 42 , Zn 2þ can simultaneously coordinate intra-and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn 2þ -Aβ 42 oligomers and thus enhances their aggregation tendency. Zn 2þ binding does not change the β-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel β-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn 2þ coordination promotes Aβ 42 aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn 2þ concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn 2þ -free solution.conformational selection | energy landscape | metal ions | modeling amyloid assemblies | seed polymorphism A lzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in millions of people worldwide (1). This disease accounts for the majority of clinical senile dementia associated with the formation of senile plaques (2, 3). The primary constituent of the plaques is the aggregated Aβ 40 ∕Aβ 42 peptides in the brain; therefore, factors that influence the aggregation are of high interest.In vivo studies reported that Zn 2þ , Cu þ2 , and Fe þ3 are markedly enriched in Aβ plaques (4, 5), suggesting that these ions may act as seeding factors. Oligomerization of the Aβ peptides can be rapidly induced in the presence of Zn 2þ ions under physiological conditions (4, 6, 7). Noy et al. (8) have followed Zn 2þ ionenhanced Aβ aggregation. Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9-26). Solution NMR of Zn 2þ -Aβ 1-16 showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ 1-28 proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22). In addition, X-ray absorption spectroscopy revealed that Zn 2þ coordinates with four histidines, H13 and H14 of two adjacent monomers (23). Experimental structural data for Aβ 40 ∕Aβ 42 oligomers complexed with Zn 2þ are unavailable.Although it is believed that reducing zinc-induced Aβ aggregation can decrease toxicity (27), it was also postulated that zinc can lower Aβ toxicity by selectively precipitating aggregation intermediates (28). Key questions on the...

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Amyloid plaques arise from zinc-enriched cortical layers in APP/PS1 transgenic mice and are paradoxically enlarged with dietary zinc deficiency

Cited by 110 publications

References 66 publications

Zinc and the aging brain

Zinc and the aging brain

Zinc, zinc transporters and diabetes

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

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