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Cited by 135Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity

Open access
Sharma, Anuj K., Pavlova, Stephanie T., Kim, Jaekwang, Kim, Jungsu, Mirica, Liviu M.·2013·Metallomics
DOI 10.1039/c3mt00161jPMC PMC4060528
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Abstract

The coordination chemistry of Cu and Zn metal ions with the amyloid β (Aβ) peptides has attracted a lot of attention in recent years due to its implications in Alzheimer's disease. A number of reports indicate that Cu and Zn have profound effects on Aβ aggregation. However, the impact of these metal ions on Aβ oligomerization and fibrillization is still not well understood, especially for the more rapidly aggregating and more neurotoxic Aβ42 peptide. Here we report the effect of Cu(2+) and Zn(2+) on Aβ42 oligomerization and aggregation using a series of methods such as Thioflavin T (ThT) fluorescence, native gel and Western blotting, transmission electron microscopy (TEM), and cellular toxicity studies. Our studies suggest that both Cu(2+) and Zn(2+) ions inhibit Aβ42 fibrillization. While presence of Cu(2+) stabilizes Aβ42 oligomers, Zn(2+) leads to formation of amorphous, non-fibrillar aggregates. The effects of temperature, buffer, and metal ion concentration and stoichiometry were also studied. Interestingly, while Cu(2+) increases the Aβ42-induced cell toxicity, Zn(2+) causes a significant decrease in Aβ42 neurotoxicity. While previous reports have indicated that Cu(2+) can disrupt β-sheets and lead to non-fibrillar Aβ aggregates, the neurotoxic consequences were not investigated in detail. The data presented herein including cellular toxicity studies strongly suggest that Cu(2+) increases the neurotoxicity of Aβ42 due to stabilization of soluble Aβ42 oligomers.

AI snapshot

Written from the paper’s full text.

TL;DR

Cu²⁺ and Zn²⁺ both inhibit Aβ42 fibrillization, but they divert aggregation toward different species: Cu²⁺ stabilizes soluble Aβ42 oligomers, whereas Zn²⁺ forms amorphous non-fibrillar aggregates. In N2A cell toxicity assays, Cu²⁺ increases Aβ42 neurotoxicity while Zn²⁺ decreases it.

Key findings

  • ThT fluorescence was significantly lower for Aβ42 aggregates formed with Cu²⁺ or Zn²⁺, while pre-formed Aβ fibrils increased ThT fluorescence by 20-fold.
  • Native gel/Western blotting and TEM showed that Cu²⁺ inhibits Aβ42 fibrillization and stabilizes small soluble Aβ42 oligomers; Zn²⁺ leads to amorphous, non-fibrillar aggregates.
  • In N2A cells, monomeric Aβ42 gave 58 ± 2% survival, preformed Aβ42 oligomers 45 ± 6%, and Aβ42 fibrils 86 ± 8%; Aβ42 + Cu²⁺ gave 48 ± 2% survival, similar to preformed oligomers.
  • Zn²⁺ reduced Aβ42 toxicity, with 80 ± 5% cell survival in both the presence and absence of Aβ42.

Methods

  • Aβ42 and Aβ40 aggregation was monitored using ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM).
  • Metal effects were tested with Cu²⁺ or Zn²⁺ at 0.25–2 equivalents relative to Aβ, under varied buffer, temperature, and incubation-time conditions.
  • Cytotoxicity was measured with the Alamar Blue assay in mouse neuroblastoma Neuro2A (N2A) cells exposed to 20 μM Aβ42 species and metal ions.

Limitations

  • The paper states that ThT fluorescence has limitations for metal–Aβ studies, including metal complex formation, paramagnetic quenching by Cu²⁺, pH effects, and inability to detect amorphous aggregates.
  • The paper notes that prior conflicting results likely arise from different experimental conditions and methods used to measure Aβ aggregation.
  • No dedicated limitations section is present; evident limitations include the in vitro aggregation assays and single N2A cell line, with no in vivo validation reported.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1039/c3mt00161j

Cites

63 of 63 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

11 of 34 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    Aβ40 does not form oligomers either in the presence or absence of metal ions.

    “Notably, the Aβ40 peptide does not form oligomers either in presence or in absence of metal ions (Fig. 2, lanes a–c), a similar behavior being observed for Aβ40 by SDS-PAGE.49”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [49] Bitan G Fradinger EA Spring SM Teplow DB Amyloid 2005 12 88 16011984 source

      The section ‘SDS-PAGE induces formation of high molecular weight Aβ assemblies’ reports that Aβ40 migrated as a monomer on SDS-PAGE, supporting the cited comparison of gel behavior. It does not establish that Aβ40 cannot form oligomers with or without metal ions. The section on SDS- and non-SDS-based methods describes cross-linked Aβ40 oligomers and cautions that SDS-PAGE can misrepresent oligomerization state. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Conflicting results have been reported for Cu2+-mediated Aβ aggregation.

    “Several studies showed that Zn2+ promotes formation of nonfibrillar aggregates,16,29–31 yet conflicting results have been reported for the Cu2+-mediated Aβ aggregation.21,28,32,33”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [21] Hureau C Coord. Chem. Rev 2012 256 2164

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28] Mold M Ouro-Gnao L Wieckowski BM Exley C Sci. Rep 2013 3 1256 23409247 PMC3570782 source
    • cites [32] Zou J Kajita K Sugimoto N Angew. Chem., Int. Ed 2001 40 2274 11433492 source
    • cites [33] Sarell CJ Wilkinson SR Viles JH J. Biol. Chem 2010 285 41533 20974842 PMC3009880 source
  • Interpretationown data

    Aβ42 oligomers are more neurotoxic than insoluble Aβ42 aggregates.

    “supporting the more neurotoxic nature of Aβ42 oligomers.60,61”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [60] Lesne S Koh MT Kotilinek L Kayed R Glabe CG Yang A Gallagher M Ashe KH Nature 2006 440 352 16541076 source
    • cites [61] Ahmed M Davis J Aucoin D Sato T Ahuja S Aimoto S Elliott JI Van Nostrand WE Smith SO Nat. Struct. Mol. Biol 2011 17 561 20383142 PMC2922021 source
  • Premisecitation

    The Alamar Blue cell assay is more appropriate for Aβ toxicity studies than the MTT assay.

    “The viability of Neuro-2A (N2A) cells57 was probed using the Alamar Blue cell assay, which was shown to be more appropriate for Aβ toxicity studies vs. the MTT assay.58,59”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [58] Wogulis M Wright S Cunningham D Chilcote T Powell K Rydel RE J. Neurosci 2005 25 1071 15689542 PMC6725948 source
    • cites [59] Stine BW Jungbauer L Yu C LaDu MJ Methods Mol. Biol 2010 670 13 20967580 PMC3752843 source

      The Materials (§2.8.1) and Methods (§3.8.1) describe an Aβ toxicity assay in N2A cells using CellTiter-Glo to measure cellular ATP. Searches for Alamar Blue and MTT found no passage comparing those assays or saying Alamar Blue is more appropriate, so our copy does not verify the attributed comparison. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
  • Findingcitation

    ThT fluorescence intensity increases by 20 fold in the presence of pre-formed Aβ fibrils.

    “The fluorescence intensity of ThT increases by 20 fold in presence of pre-formed Aβ fibrils (Fig. 1), as observed previously for similar Aβ42 peptide concentrations.32”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Zou J Kajita K Sugimoto N Angew. Chem., Int. Ed 2001 40 2274 11433492 source
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Interpretationcitation

    The decreased ThT fluorescence in the presence of Cu2+ can be accounted for by less fibril formation, although quenching by paramagnetic Cu2+ could also be involved.

    “A decreased ThT fluorescence32,36 in presence of Cu2+ ions can be accounted for by less fibril formation, although a quenching of fluorescence by the paramagnetic Cu2+ ions could also be involved.47”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [32] Zou J Kajita K Sugimoto N Angew. Chem., Int. Ed 2001 40 2274 11433492 source
    • cites [36] House E Mold M Collingwood J Baldwin A Goodwin S Exley C J. Alzheimers Dis 2009 18 811 19749401 PMC2857508 source

      Citation 47 is attached to the possibility that paramagnetic Cu2+ quenches ThT fluorescence. The Discussion (page unavailable) attributes the decrease to changes in preformed fibrils and reports no evidence about paramagnetic quenching; a search for quenching and paramagnetism found no passage addressing that possibility. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [47] Pradines V Stroia AJ Faller P New J. Chem 2008 32 1189

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Soluble Aβ oligomers are more neurotoxic than amyloid plaques and most likely responsible for synaptic dysfunction and memory loss in AD.

    “However, recent in vivo studies have shown that soluble Aβ oligomers are more neurotoxic than amyloid plaques and most likely responsible for synaptic dysfunction and memory loss in AD.7–11”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [7] Walsh DM Selkoe DJ J. Neurochem 2007 101 1172 17286590 source
    • cites [8] Haass C Selkoe DJ Nat. Rev.: Mol. Cell Biol 2007 8 101 17245412 source
    • cites [9] Borutaite V Morkuniene R Valincius G BioMol Concepts 2011 2 211 25962030 source
    • cites [10] Lambert MP Barlow AK Chromy BA Edwards C Freed R Liosatos M Morgan TE Rozovsky I Trommer B Viola KL Wals P Zhang C Finch CE Krafft GA Klein WL Proc. Natl. Acad. Sci. U. S. A 1998 95 6448 9600986 PMC27787 source
    • cites [11] Gong YS Chang L Viola KL Lacor PN Lambert MP Finch CE Krafft GA Klein WL Proc. Natl. Acad. Sci. U. S. A 2003 100 10417 12925731 PMC193576 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Zn2+ promotes formation of nonfibrillar aggregates.

    “Several studies showed that Zn2+ promotes formation of nonfibrillar aggregates,16,29–31 yet conflicting results have been reported for the Cu2+-mediated Aβ aggregation.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [16] Bush AI Pettingell WH Multhaup G Paradis MD Vonsattel JP Gusella JF Beyreuther K Masters CL Tanzi RE Science 1994 265 1464 8073293 source
    • cites [29] Sharma AK Pavlova ST Kim J Finkelstein D Hawco NJ Rath NP Kim J Mirica LM J. Am. Chem. Soc 2012 134 6625 22452395 PMC3368506 source
    • cites [30] Garai K Sahoo B Kaushalya SK Desai R Maiti S Biochemistry 2007 46 10655 17718543 source
    • cites [31] Tõugu V Karafin A Zovo K Chung RS Howells C West AK Palumaa P J. Neurochem 2009 110 1784 19619132 source

  • May combine two claims.

    Premisecitation

    Aβ42 is more neurotoxic and has a higher tendency to aggregate than Aβ40.

    “Although Aβ40 is present in larger amounts in the brain, Aβ42 was found to be more neurotoxic and have a higher tendency to aggregate.4,5”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [4] McGowan E Pickford F Kim J Onstead L Eriksen J Yu C Skipper L Murphy MP Beard J Das P Jansen K DeLucia M Lin WL Dolios G Wang R Eckman CB Dickson DW Hutton M Hardy J Golde T Neuron 2005 47 191 16039562 PMC1373682 source
    • cites [5] Kuperstein I Broersen K Benilova I Rozenski J Jonckheere W Debulpaep M Vandersteen A Segers-Nolten I Van Der Werf K Subramaniam V Braeken D Callewaert G Bartic C D’Hooge R Martins IC Rousseau F Schymkowitz J De Strooper B EMBO J 2010 29 3408 20818335 PMC2957213 source

  • May combine two claims.

    Findingown data

    The presence of Cu2+ limits the formation of insoluble aggregates and high MW oligomers and seems to stabilize small MW oligomers at room temperature.

    “However, the presence of Cu2+ limits the formation of insoluble aggregates and high MW oligomers and seems to stabilize small MW oligomers (Fig. 4, panel b and lane b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the presence of Cu2+, Aβ40 forms fibrils although in a lower amount, and the nature of aggregates formed remains fibrillar.

    “In presence of Cu2+, Aβ40 forms fibrils although in a lower amount as observed by TEM, yet the nature of aggregates formed remains fibrillar (Fig. 2, panel b).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Western blot confirms the formation of small soluble Aβ42 oligomers in the presence of Cu2+, and the formation of high MW oligomers is inhibited.

    “Western blot confirms the formation of small soluble Aβ42 oligomers (lane e), the formation of high MW oligomers being inhibited.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 37 °C, Aβ42 forms amyloid fibrils within 24 h and large MW oligomers.

    “At 37 °C the Aβ42 peptide forms amyloid fibrils within 24 h as observed in TEM, as well as large MW oligomers as seen in the Western blot (Fig. 4, panel c and lane c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    0.25 equiv Cu2+ does not completely inhibit Aβ42 aggregation, while Cu2+ amounts larger than 0.5 equiv lead to formation of soluble Aβ42 species.

    “While the presence of 0.25 equiv. Cu2+ (6.25 μM) does not completely inhibit Aβ42 aggregation, Cu2+ amounts larger than 0.5 equiv. lead to formation of soluble Aβ42 species.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Western blotting of Zn2+-Aβ42 aggregates shows formation of small soluble Aβ42 oligomers, while high MW oligomers were not observed.

    “Western blotting of Zn2+-Aβ42 aggregates shows formation of small soluble Aβ42 oligomers, while high MW oligomers were not observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The Western blot of Aβ42 shows formation of various size oligomers (trimer, tetramer, and higher MW oligomers) as well as a small band at gel entrance.

    “The Western blot of Aβ42 shows formation of various size oligomers (trimer, tetramer, and higher MW oligomers) as well as a small band at gel entrance (lane d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The presence of Cu2+ leads to formation of small MW oligomers at 37 °C, suggesting that Cu2+ stabilizes Aβ42 oligomers even at 37 °C.

    “By contrast, the presence of Cu2+ leads to formation of small MW oligomers, which suggests that Cu2+ stabilizes Aβ42 oligomers even at 37 °C (Fig. 4, lane d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aβ42 forms amorphous aggregates after incubation for 72 h at room temperature and forms a range of soluble oligomers.

    “Aβ42 forms amorphous aggregates after incubation for 72 h at room temperature and forms a range of soluble oligomers (Fig. 4, panel a and lane a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cu2+ was not toxic to cells in the absence of Aβ42, with 90 × 5% cell survival observed in the presence of Cu2+.

    “While Cu2+ was not toxic to cells in the absence of Aβ42 – a 90 × 5% cell survival being observed in presence of Cu2+ (Fig. 8, lane 4), a markedly reduced 48 ± 2% cell survival was observed in the presence of Aβ42 and Cu2+ (Fig. 8, lane 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The presence of Cu2+ inhibits formation of the large MW oligomers and selectively stabilizes small MW oligomers even after four days.

    “Interestingly, the presence of Cu2+ seems to inhibit formation of the large MW oligomers and selectively stabilizes small MW oligomers, even after four days (Fig. 7A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The presence of Cu2+ leads to a statistically significant decrease in cell viability, similar to that observed for preformed Aβ42 oligomers.

    “Thus, the presence of Cu2+ leads to a statistically significant decrease in cell viability, which is similar to that observed for preformed Aβ42 oligomers (Fig. 8, lane 5 vs. lane 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Zn2+ leads to disappearance of high MW oligomers, only small Aβ42 oligomers being observed, likely along with an appreciable amount of insoluble amorphous aggregates.

    “On the other hand, Zn2+ leads to disappearance of high MW oligomers, only small Aβ42 oligomers being observed (Fig. 7B) that form likely along with an appreciable amount of insoluble amorphous aggregates (Fig. 6).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Study design and conductnone given

    The TEM images in Fig. 5 are representative of the entire surface of TEM grids that show a homogeneous distribution of the observed Aβ species.

    “Importantly, the TEM images in Fig. 5 are representative of the entire surface of TEM grids that show a homogeneous distribution of the observed Aβ species.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Cu2+ has an inhibitory effect on Aβ42 fibrillization and leads to the formation of soluble Aβ42 oligomers.

    “Overall, both TEM and native gel/Western blotting studies strongly suggest that Cu2+ has an inhibitory effect on Aβ42 fibrillization and leads to the formation of soluble Aβ42 oligomers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Metal ions promote Aβ aggregation and formation of reactive oxygen species and lead to oxidative stress.

    “For example, it was shown that that metal ions promote Aβ aggregation,16,17 as well as formation of reactive oxygen species (ROS) and lead to oxidative stress.18–20”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [16] Bush AI Pettingell WH Multhaup G Paradis MD Vonsattel JP Gusella JF Beyreuther K Masters CL Tanzi RE Science 1994 265 1464 8073293 source
    • cites [17] Atwood CS Moir RD Huang XD Scarpa RC Bacarra NME Romano DM Hartshorn MK Tanzi RE Bush AI J. Biol. Chem 1998 273 12817 9582309 source
    • cites [18] Hureau C Faller P Biochimie 2009 91 1212 19332103 source
    • cites [19] Zhu X Su B Wang X Smith M Perry G Cell. Mol. Life Sci 2007 64 2202 17605000 PMC11136009 source
    • cites [20] Crichton RR Dexter DT Ward RJ Coord. Chem. Rev 2008 252 1189

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study employed a wide range of techniques (ThT fluorescence, native gel electrophoresis and Western blotting, TEM, and cellular toxicity studies) to study the effect of metal ions on Aβ42 oligomerization and aggregation.

    “Herein we have employed for the first time a wide range of techniques to study the effect of metal ions on the oligomerization and aggregation of the more neurotoxic Aβ42 peptide.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All solutions and buffers were prepared using metal-free Millipore water treated with Chelex and filtered to avoid metal contamination.

    “All solutions and buffers were prepared using metal-free Millipore water that was treated with Chelex overnight and filtered through a 0.22 μm nylon filter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Even a substoichiometric amount of Zn2+ dramatically affects Aβ42 fibrillization and leads to formation of amorphous Aβ42 aggregates instead of soluble oligomers.

    “The experiment suggests that even a substoichiometric amount of Zn2+ dramatically affects Aβ42 fibrillization and leads to formtion of amorphous Aβ42 aggregates instead of soluble oligomers.”
    Quote in the paperSubstantial claim
23 of 23

  • The paper relies on this without support.

    In vitro Aβ42 aggregation and cell toxicity results can be extrapolated to the in vivo role of metal–Aβ42 interactions in AD.

    “Most importantly, we have correlated these in vitro results with neurotoxicity studies, in order to address to potential in vivo role of metal–Aβ42 interactions in AD.”
    “These studies rule out a preventive role of Cu2+ and suggest that Cu2+ may lead to an increased Aβ42 neurotoxicity in vivo due to formation of Aβ42 oligomers.”

  • The paper relies on this without support.

    The neurotoxic Aβ42 oligomers formed in vitro are the same species responsible for neurotoxicity in AD.

    “The data presented herein including cellular toxicity studies strongly suggest that Cu2+ increases the neurotoxicity of Aβ42 due to stabilization of soluble Aβ42 oligomers.”
    “Thus, this Cu2+-promoted increased neurotoxicity of soluble Aβ42 species may play an important role in the etiology of AD.”

  • The paper relies on this without support.

    Viability of Neuro-2A cells is a valid measure of Aβ42 neurotoxicity relevant to Alzheimer’s disease.

    “The viability of Neuro-2A (N2A) cells57 was probed using the Alamar Blue cell assay, which was shown to be more appropriate for Aβ toxicity studies vs. the MTT assay.58,59”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The majority of these BFCs have been studied for their effect on aggregation of the Aβ40 peptide, and fewer studies have focused on their interaction with the more neurotoxic Aβ42 peptide.

    “However, the majority of these BFCs have been studied for their effect on aggregation of the Aβ40 peptide,25,31 and fewer studies have focused on their interaction with the more neurotoxic Aβ42 peptide.20,21”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [21]

    The Introduction (page unavailable) says Aβ42 is more neurotoxic than Aβ40, and the Results and discussion section says this study focuses mainly on how Cu2+ and Zn2+ affect Aβ42 aggregation. The cited paper does not establish that fewer studies have examined BFC interactions with Aβ42, nor does it study BFCs itself. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • In inhibition experiments, reduced ThT fluorescence was observed for Cu2+- and Zn2+-containing fibrils.

    “In inhibition experiments, a reduced ThT fluorescence was observed for the Cu2+- and Zn2+-containing fibrils, as reported previously (Figure 6).21,49,50”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [21]

    The Introduction and the Results and discussion section on ThT fluorescence report reduced fluorescence for Aβ42 aggregates prepared with Cu2+ and Zn2+. They do not establish that the measured material was fibrils: the paper says the metals inhibit fibrillization, with Zn2+ promoting amorphous aggregates and Cu2+ stabilizing soluble species. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The approach of inhibiting metal-mediated Aβ40 aggregation or promoting disaggregation may not be optimal for the Aβ42 peptide, given the increased toxicity observed for soluble Aβ42 oligomers.

    “However, this approach may not be optimal for the Aβ42 peptide, given the increased toxicity observed for soluble Aβ42 oligomers.20,21”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [21]

  • Cu2+ ions slow down fibrillization of Aβ42 peptide and stabilize soluble Aβ42 species.

    “We have also recently reported that Cu2+ ions slow down fibrillization of the Aβ42 peptide and stabilize the soluble Aβ42 species, as observed by native gel electrophoresis/Western blotting, TEM, cell viability studies,20,21 and pulsed hydrogen/deuterium exchange mass spectrometry studies.22”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [21]

  • The presence of Cu2+ ions inhibits the formation of large soluble and insoluble Aβ42 aggregates.

    “the presence of Cu2+ ions inhibits the formation of large soluble and insoluble Aβ42 aggregates (Figure 7, lane 2).”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [21]

Self-check

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Self-check results appear here once an independent check has confirmed them.

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1038/nature04533

    Info

    The cited work was retracted on 2024-06-24 (notice 10.1038/s41586-024-07691-8), not before this paper was published (2013).

    Cited work 10.1038/nature04533 · retracted 2024-06-24 · notice 10.1038/s41586-024-07691-8 · this paper published 2013

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Related

Authors
Sharma, A. K., Pavlova, S. T., Kim, J., Kim, J., & Mirica, L. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Mirica, Liviu M.
ORCID
Venue
Metallomics
Publisher
Oxford University Press (OUP)
Published
2013
Volume
5
Issue
11
Pages
1529
ISSN
  • 1756-5901 (ISSN-L)
  • 1756-591X
DOI
10.1039/c3mt00161j
PMC
PMC4060528
OpenAlex
W2027527679
Semantic Scholar
979734017be9e607107cd2303763e2725cc3e615
Cited by
135
References
64
Citations by year
2026: 8 · 2025: 6 · 2024: 12 · 2023: 8 · 2022: 20 · 2021: 5 · 2020: 15 · 2019: 11 · 2018: 9 · 2017: 11 · 2016: 11 · 2015: 9 · 2014: 9 · 2013: 1
FWCI
6.12
Type
journal article
Language
en
Open access
Locations
  • Metallomics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institutes of Health (5p41rr000954-34)
  • National Center for Research Resources (P41-RR000954)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-beta 42, copper ions, zinc ions, metal-peptide coordination, peptide aggregation, oligomerization, fibrillization, neurotoxicity, Alzheimer's disease, amorphous aggregates
MeSH terms
Animals, Cell Survival, Copper, Fluorescence, Protein Binding, Thiazoles, Zinc, Amyloid beta-Peptides, Cell Line, Tumor, Mice, Benzothiazoles

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