Examining the zinc binding site of the amyloid‐β peptide

Yang, Dun‐Sheng; McLaurin, JoAnne; Qin, Ken; Westaway, David; Fraser, Paul E.

doi:10.1046/j.1432-1327.2000.01767.x

Cited by 120 publications

(111 citation statements)

References 47 publications

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“…Evidences obtained in vitro suggest that zinc may contribute to A␤ aggregation and thus plaque formation (5)(6)(7)(8). The recent demonstration that metal chelation ameliorates A␤ plaque formation in hAPP ϩ mice strongly supports this hypothesis (13).…”

Section: Discussionmentioning

confidence: 89%

See 1 more Smart Citation

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Lee

Cole

Palmiter

et al. 2002

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

393

280

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Endogenous metals may contribute to the accumulation of amyloid plaques in Alzheimer's disease. To specifically examine the role of synaptic zinc in the plaque accumulation, Tg2576 (also called APP2576) transgenic mice (hAPP ؉ ) expressing cerebral amyloid plaque pathology were crossed with mice lacking zinc transporter 3 (ZnT3 ؊/؊ ), which is required for zinc transport into synaptic vesicles. With aging, female hAPP ؉ :ZnT3 ؉/؉ mice manifested higher levels of synaptic zinc, insoluble amyloid ␤, and plaques than males; these sex differences disappeared in hAPP ؉ :ZnT3 ؊/؊ mice. Both sexes of hAPP ؉ :ZnT3 ؊/؊ mice had markedly reduced plaque load and less insoluble amyloid ␤ compared with hAPP ؉ :ZnT3 ؉/؉ mice. Hence, of endogenous metals, synaptic zinc contributes predominantly to amyloid deposition in hAPP ؉ mice.

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Section: Discussionmentioning

confidence: 89%

“…First, zinc or copper induces the rapid aggregation of synthetic A␤ in an aqueous environment (5,6), likely by binding to histidine residues within A␤ (7,8). Second, concentrations of the transition metals including zinc and copper are elevated in AD brains, more so around plaques (9)(10)(11).…”

mentioning

confidence: 99%

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Lee

Cole

Palmiter

et al. 2002

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

393

280

View full text Add to dashboard Cite

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“…a change of conformation induced by metal ions on IDE substrates can produce proteolytic resistant species. In this respect, it has been reported that zinc, but not copper, induces the formation of Aβ aggregates resistant to IDE proteolytic action [35,36]. These data indicate that external factors, such as high metal concentrations that promote Aβ aggregate formation, may contribute to Aβ accumulation by decreasing the peptide's sensitivity to proteolytic degradation; ii.…”

Section: Introductionmentioning

confidence: 90%

Metal ions affect insulin-degrading enzyme activity

Grasso

Salomone

Tundo

et al. 2012

Journal of Inorganic Biochemistry

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Insulin degradation is a finely tuned process that plays a major role in controlling insulin action and most evidence supports IDE (insulin-degrading enzyme) as the primary degradative agent. However, the biomolecular mechanisms involved in the interaction between IDE and its substrates are often obscure, rendering the specific enzyme activity quite difficult to target. On the other hand, biometals, such as copper, aluminum and zinc, have an important role in pathological conditions such as Alzheimer's disease or diabetes mellitus. The metabolic disorders connected with the latter lead to some metallostasis alterations in the human body and many studies point at a high level of interdependence between diabetes and several cations. We have previously reported (Grasso et al., Chem. Eur. J. 17 (2011) 2752-2762) that IDE activity toward Aβ peptides can be modulated by metal ions. Here, we have investigated the effects of different metal ions on the IDE proteolytic activity toward insulin as well as a designed peptide comprising a portion of the insulin B chain (B20-30), which has a very low affinity for metal ions. The results obtained by different experimental techniques clearly show that IDE is irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound to copper(II).

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“…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.

280

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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Examining the zinc binding site of the amyloid‐β peptide

Cited by 120 publications

References 47 publications

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice

Metal ions affect insulin-degrading enzyme activity

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

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