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Cited by 48Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesMolecular Sensors and Ion Detection

Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity

Open access
Sharma, Anuj K., Kim, Jaekwang, Prior, John T., Hawco, Nicholas J., Rath, Nigam P., Kim, Jungsu, Mirica, Liviu M.·2014·Inorganic Chemistry
DOI 10.1021/ic500926cPMC PMC4220862
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Abstract

Multifunctional metal chelators that can modulate the amyloid β (Aβ) peptide aggregation and its interaction with metal ions such as copper and zinc hold considerable promise as therapeutic agents for Alzheimer’s disease (AD). However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects. Reported herein are two novel small bifunctional chelators, 2-[2-hydroxy-4-(diethylamino)phenyl]benzothiazole (L1) and 2-(2-hydroxy-3-methoxyphenyl)benzothiazole (L2), in which the metal-binding donor atoms are integrated within a molecular framework derived from the amyloid-binding fluorescent dye thioflavin T (ThT). The metal-binding properties of L1 and L2 were probed by pH spectrophotometric titrations to determine their pKa values and the corresponding metal complex stability constants, and the isolated metal complexes were structurally characterized. The amyloid-fibril-binding properties of L1 and L2 were investigated by fluorescence titrations and ThT competition assays. Interestingly, L1 and L2 do not lead to the formation of neurotoxic Aβ42 oligomers in the presence or absence of metal ions, as observed by native gel electrophoresis, Western blotting, and transmission electron microscopy. In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers and of the copper-stabilized Aβ42 oligomers. Given their ability to reduce the toxicity of soluble Aβ42 and Cu-Aβ42 species, L1 and L2 are promising lead compounds for the development of chemical agents that can control the neurotoxicity of soluble Aβ42 species in AD.

AI snapshot

Written from the paper’s full text.

TL;DR

Two small bifunctional chelators, L1 and L2, were designed to bind both metal ions and amyloid β (Aβ) fibrils without disaggregating them. They reduced the cellular toxicity of preformed Aβ42 oligomers and copper-stabilized Aβ42 oligomers in N2A cells.

Key findings

  • L1 and L2 bind Aβ fibrils with moderate to strong affinity: L1 gave a Kd of 4.70 ± 0.30 μM and a ThT-competition Ki of 260 ± 40 nM; L2 gave a Ki of 15 ± 10 nM.
  • L1 pKa values were 3.556(2), 8.427(3), and 10.108(2); L2 pKa values were 3.154(2) and 9.360(1). L1 binds Cu2+ with log stability constants of 11.99(2) for ML and 20.99(2) for ML2, with pCu values of 6.7 at pH 6.6 and 8.2 at pH 7.4.
  • L1 and L2 did not promote formation of soluble Aβ42 oligomers in the presence or absence of metal ions; with Cu2+ they promoted formation of larger insoluble Aβ42 aggregates, and they did not appreciably disaggregate preformed Aβ42 fibrils.
  • In N2A cells, preformed Aβ42 oligomers reduced survival to 45 ± 6%; addition of L1 or L2 restored viability to 100 ± 15% and 103 ± 15%, respectively, including in the presence of Cu2+. Clioquinol with Aβ42 fibrils plus Cu2+ gave only 26 ± 3% survival.

Methods

  • L1 and L2 were synthesized and characterized by NMR, UV–vis, ESI-MS, elemental analysis, pH spectrophotometric titrations, Job’s plots, and X-ray crystallography of Cu2+ and Zn2+ complexes.
  • Aβ fibril binding was measured by fluorescence titrations and ThT competition assays using Aβ40 fibrils; Aβ42 aggregation, inhibition, and disaggregation were assessed by ThT fluorescence, native gel electrophoresis/Western blotting, and TEM.
  • Cytotoxicity was measured in mouse neuroblastoma N2A cells using the Alamar Blue assay with 20 μM Aβ42 species, compounds, and metals, after 40 h incubation.

Limitations

  • Stated in the paper: Zn2+ stability constants could not be determined because L1 and L2 showed almost no spectral changes with Zn2+ and did not compete significantly with zincon; L2–Cu2+ titration was limited by few spectral changes at micromolar concentrations and precipitation at higher concentrations; pure zinc complexes of L1 or L2 could not be isolated for complete characterization.
  • Stated in the paper: the work is in vitro, and in vivo studies are described as ongoing; no in vivo efficacy or toxicity data are reported.
  • Evident from the text: Aβ40 was used for fibril-binding assays while Aβ42 was used for aggregation and toxicity studies, and the Aβ40 aggregation results were noted to be less informative because of the lack of appreciable soluble Aβ oligomer formation.

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

Integrity signals

Registry

Crossref · 10.1021/ic500926c

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

40 of 85 cited sources checked · 23 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Soluble Aβ oligomers are more neurotoxic than insoluble aggregates both in vitro and in vivo.

    “recent studies have shown that the soluble Aβ oligomers are more neurotoxic both in vitro and in vivo.5−8”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [5] Walsh, 2007, J. Neurochem. source

      In “Detection and toxicity of non-fibrillar assemblies of synthetic Aβ” (page not provided), the review reports that oligomers caused substantially faster and greater neuronal death in culture than fibrillar Aβ. It also describes brain dysfunction caused by soluble oligomers in animals in “Aβ self-association is required for toxicity” (page not provided), but does not establish that they are more neurotoxic than insoluble aggregates in vivo. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [6] Haass, 2007, Nat. Rev. Mol. Cell Biol. source
    • cites [7] Lambert, 1998, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [8] Gong, 2003, Proc. Natl. Acad. Sci. U.S.A. source
  • Premisecitation

    Molecules having log BB values higher than −0.3 are generally expected to cross the BBB.

    “Molecules having log BB values higher than −0.3 are generally expected to cross the BBB.33”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Rodriguez-Rodriguez, 2009, J. Am. Chem. Soc. source
  • Interpretationcitation

    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”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source
    • cites [21] Sharma, 2013, Metallomics source
  • Findingcitation

    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).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source

      In Results and Discussion, ‘Effect of L1 and L2 on Aβ42 Aggregation’ (page unavailable), the paper reports almost no fibrils after 24 hours in the presence of Cu, supporting inhibition of large insoluble aggregates. It also reports soluble Aβ42 oligomers of 10–110 kDa and says metal ions stabilize soluble oligomers, so it does not support inhibition of large soluble aggregates. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [21] Sharma, 2013, Metallomics source
  • Premisecitation

    Cu2+-Aβ species have been shown to be neurotoxic.

    “Because Cu2+–Aβ species have been shown to be neurotoxic,20,21,31,51,52”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source
    • cites [21] Sharma, 2013, Metallomics source
    • cites [31] Hindo, 2009, J. Am. Chem. Soc. source
    • cites [51] Bush, 2002, Neurobiol. Aging source
    • cites [52] Huang, 1999, J. Biol. Chem. source
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 49

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

    Premisecitation

    The longer and more hydrophobic Aβ42 isoform has a higher tendency to generate neurotoxic oligomeric species than Aβ40.

    “the longer and more hydrophobic Aβ42 isoform has a higher tendency to generate neurotoxic oligomeric species.9,10”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] McGowan, 2005, Neuron source
    • cites [10] Kuperstein, 2010, EMBO J. source

      The ‘Long-term cellular toxicity of Aβ mixtures’ section reports neurotoxicity from Aβ42 alone but not Aβ40 alone; the discussion links Aβ42-rich preparations to toxic intermediates. This supports the comparative tendency, but our copy does not establish that Aβ42’s greater hydrophobicity explains it, and emphasizes the importance of the Aβ42:Aβ40 ratio. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    We have recently reported 2-phenylbenzothiazole/vanillin derivatives as BFCs that showed a strong affinity for Aβ fibrils.

    “We have also recently reported 2-phenylbenzothiazole/vanillin derivatives as BFCs that showed a strong affinity for Aβ fibrils.20”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    In Rodríguez-Rodríguez et al., only solution coordination properties were investigated in detail, while Aβ-binding and antiaggregation properties were only qualitatively evaluated through epifluorescence microscopy and turbidity assays.

    “However, in that report, only the solution coordination properties of those compounds were investigated in detail, while the Aβ-binding and antiaggregation properties were only qualitatively evaluated through epifluorecense microscopy and turbidity assays.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Rodriguez-Rodriguez, 2009, J. Am. Chem. Soc. source

      The Fluorescence Microscopy Binding Assays section describes imaging fibrils, and the Figure 10 caption (p. 40) explicitly calls its binding-intensity scale qualitative. The paper also investigates aggregation with turbidity assays, but the Turbidity Measurements section reports repeated, blank-corrected absorbance measurements, and the aggregation discussion gives a numerical result. Thus, describing the antiaggregation evaluation as only qualitative overstates the source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Previously, an iodinated HPB and related compounds were shown to have potential as metal-chelating agents by Rodríguez-Rodríguez et al.

    “Previously, an iodinated HPB and a few related compounds were shown to have potential as metal-chelating agents by Rodríguez-Rodríguez et al.33”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Rodriguez-Rodriguez, 2009, J. Am. Chem. Soc. source

      The Summary (page not available) reports that the iodinated compounds HBXI, HBTI and BMI can chelate Cu(II) and Zn(II), supporting the metal-chelating point. Our copy identifies these compounds as derivatives of HBX, HBT and BM; it does not identify an iodinated compound called HPB. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Compounds that inhibit metal-mediated Aβ40 aggregation or promote disaggregation of amyloid fibrils lead to increased cell viability.

    “Compounds that inhibit metal-mediated Aβ40 aggregation or promote disaggregation of amyloid fibrils were shown to lead to increased cell viability.25,31,32”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [25] Choi, 2010, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [31] Hindo, 2009, J. Am. Chem. Soc. source

      In the main text (page unavailable), compounds 1 and 2 inhibit Cu-induced Aβ aggregation and disassemble Cu-Aβ fibrils; a separate cell experiment reports that compound 2 reduces Cu-Aβ toxicity, yielding about 90% cell survival. The paper does not establish that aggregation inhibition or fibril disaggregation caused the improved survival, or that the result applies to such compounds generally. Our copy identifies the peptide in these passages as Aβ, not specifically Aβ40. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [32] Scott, 2011, Chem. Sci. source

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source
    • cites [21] Sharma, 2013, Metallomics source
    • cites [22] Zhang, 2013, Proc. Natl. Acad. Sci. U.S.A. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent efforts to control abnormal Aβ-metal interactions have focused on small molecules, bifunctional chelators (BFCs), that have binding affinity for both metal ions and Aβ aggregates.

    “Recent efforts to control abnormal Aβ–metal interactions have focused on small molecules, bifunctional chelators (BFCs), that have binding affinity for both metal ions and Aβ aggregates.20,25,27−30”
    Quote in the paperSubstantial claim2 of 6 sources checked
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source
    • cites [25] Choi, 2010, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [27] Dedeoglu, 2004, Exp. Gerontol. source
    • cites [28] Liu, 2013, Inorg. Chem. source
    • cites [29] Pithadia, 2012, Curr. Opin. Chem. Biol. source
    • cites [30] Pithadia, 2012, Inorg. Chem. source

  • May combine two claims.

    Premisecitation

    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”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [25] Choi, 2010, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [31] Hindo, 2009, J. Am. Chem. Soc. source

      The main text (page unavailable) reports that bifunctional chelators 1 and 2 modulate copper-induced Aβ aggregation, supporting this paper as an example of such a study. It identifies the peptide only as Aβ; our copy does not establish that it was Aβ40 or support the claim that a majority of BFC studies used Aβ40 rather than Aβ42 (searched both peptide names). (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [20] Sharma, 2012, J. Am. Chem. Soc. source
    • cites [21] Sharma, 2013, Metallomics source

      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

  • May combine two claims.

    Premisecitation

    Metal chelators reduce metal-mediated Aβ aggregation, ROS formation, and neurotoxicity in vitro.

    “metal chelators have been shown to reduce metal-mediated Aβ aggregation, ROS formation, and neurotoxicity in vitro.23−26”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [23] Rodríguez-Rodríguez, 2012, Coord. Chem. Rev. source
    • cites [24] Braymer, 2011, Int. J. Alzheimer’s Dis. source
    • cites [25] Choi, 2010, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [26] Scott, 2009, Chem. Rev. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Aβ42 peptide is more prone to form neurotoxic soluble Aβ oligomers than the Aβ40 peptide.

    “Although it was shown in previous studies9,10,21 that the Aβ42 peptide is more prone to form neurotoxic soluble Aβ oligomers than the Aβ40 peptide”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [9] McGowan, 2005, Neuron source
    • cites [10] Kuperstein, 2010, EMBO J. source
    • cites [21] Sharma, 2013, Metallomics source

  • May combine two claims.

    Findingcitation

    The presence of Cu2+ and Zn2+ does not inhibit Aβ40 aggregation, yet they change the morphology of the insoluble aggregates that become more amorphous.

    “the presence of Cu2+ and Zn2+ does not inhibit Aβ40 aggregation,21 yet they change the morphology of the insoluble aggregates that become more amorphous (Figure S9 in the SI, panels 2 and 3).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Sharma, 2013, Metallomics source

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

    Interpretationreasoning

    The pCu values for Cu-L1 are lower than those for the analogous HPB compound reported previously.

    “These pCu values are lower compared to those for the analogous HPB compound reported previously,33”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Rodriguez-Rodriguez, 2009, J. Am. Chem. Soc. source

      The metal-binding discussion (section <TABLE 5> <FIGURE 8>, page unavailable) describes pM values for HBXI, HBTI, and BMI, while Table 5 lists their stability constants. Searches for Cu-L1, HPB, and their pCu comparison found no passage addressing whether Cu-L1 has lower pCu values than HPB. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Aβ40 fibrils form more homogeneous fibrillar structures without any nonfibrillar aggregates.

    “These studies were performed with Aβ40 fibrils, which form more homogeneous fibrillar structures without any nonfibrillar aggregates.45,47”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [45] Klunk, 2001, Life Sci. source
    • cites [47] Lockhart, 2005, J. Biol. Chem. source

      The Materials and Methods section (page not provided) confirms that the authors prepared Aβ40 fibrils. The section on binding constants (page not provided) reports uniformly distributed ligand-binding sites, but also identifies two populations of high-molecular-mass species. It does not establish that the fibrillar structures are more homogeneous or free of nonfibrillar aggregates. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    The Ki value for L1 is smaller than the Kd value, most likely because ThT binds with different affinities to more than one site on Aβ fibrils.

    “It should be noted that the Ki value for L1 is smaller than the Kd value, which is most likely due to the fact that ThT binds with different affinities to more than one site to the Aβ fibrils.47”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [47] Lockhart, 2005, J. Biol. Chem. source

      The Discussion (page unavailable) reports multiple ligand-binding sites on Aβ fibrils and differences between fluorescence- and radioligand-derived binding values, supporting the proposed explanation in general. However, the paper does not report a Ki or Kd for L1 or establish that its particular Ki–Kd difference is caused by ThT binding at sites with different affinities. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    The clinically tested compound CQ was quite toxic to cells even at 2 μM concentration, while EDTA does not show any toxicity up to 20 μM.

    “the clinically tested compound CQ was quite toxic to cells even at 2 μM concentration, while EDTA does not show any toxicity up to 20 μM.25,31”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [25] Choi, 2010, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [31] Hindo, 2009, J. Am. Chem. Soc. source

      The cell-study passage (page not provided) reports that CQ was more toxic than the paper’s chelators 1 and 2 in the presence of CuII. It does not establish toxicity at 2 μM or report that EDTA was nontoxic up to 20 μM; the stated absence of toxicity up to 200 μM refers to compound 2, not EDTA. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The calculated log BB values for L1 and L2 are +0.33 and +0.087, respectively.

    “The calculated log BB values for L1 and L2 are +0.33 and +0.087, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both L1 and L2 are small in size and satisfy Lipinski's rules for crossing the BBB.

    “Both L1 and L2 are small in size, and they also satisfy Lipinski’s rules for crossing the BBB (Table 1).”
    Quote in the paperSubstantial claim

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

    Findingown data

    L1 and L2 exhibit UV absorption in MeCN at 260 and 380 nm for L1 and at 305 and 345 nm for L2.

    “These compounds exhibit UV absorption in MeCN at 260 and 380 nm for L1 and at 305 and 345 nm for L2 (Figures S1 and S2 in the SI).40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

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

  • May combine two claims.

    Findingown data

    L1 and L2 reduce the cell toxicity of preformed Aβ42 oligomers and of copper-stabilized Aβ42 oligomers.

    “In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers and of the copper-stabilized Aβ42 oligomers.”
    • Also stated in: § Introduction · plain
      “In addition, L1 and L2 were able to reduce the cell toxicity of preformed Aβ42 oligomers as well as that of soluble copper-stabilized Aβ42 oligomers, which were shown recently to be neurotoxic.20,21”
    Quote in the paperSubstantial claim

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

    Findingown data

    For L1, the best fit to the UV-vis titration data was obtained with pKa values of 3.556(2), 8.427(3), and 10.108(2).

    “For L1, the best fit to the data was obtained with pKa values of 3.556(2), 8.427(3), and 10.108(2) (Table 2).”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    L1 exhibits low-intensity emission at 450 nm and a shoulder at 525 nm, while L2 shows a more intense emission at 525 nm in PBS.

    “While both L1 and L2 are 2-phenylbenzothiazole derivatives, L1 exhibits low-intensity emission at 450 nm and a shoulder at 525 nm, yet L2 shows a more intense emission at 525 nm in PBS (Figures S3 and S4 in the SI).40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

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

  • May combine two claims.

    Findingown data

    L1 exhibits an acceptable binding affinity for Aβ fibrils, with the higher affinity binding site corresponding to a Ki of 260 nM.

    “While L1 exhibits an acceptable binding affinity for Aβ fibrils, with the higher affinity binding site corresponding to a Ki of 260 nM”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For the Cu-L1 system, pCu values are 6.7 at pH 6.6 and 8.2 at pH 7.4.

    “pCu values of 6.7 and 8.2 being determined for the Cu–L1 system at pH 6.6 and 7.4, respectively”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Although a single crystal suitable for X-ray crystallography could be obtained from the reaction mixture of L1 and Zn2+, the isolation of the zinc complexes of L1 or L2 did not lead to pure complexes to allow for their complete characterization.

    “Although a single crystal suitable for X-ray crystallography could be obtained from the reaction mixture of L1 and Zn2+, the isolation of the zinc complexes of L1 or L2 did not lead to pure complexes to allow for their complete characterization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In complex 3, an oxygen and a nitrogen atom from two ligand molecules coordinate to Cu2+, with Cu-O1 and Cu-N1 bond lengths of 1.873(4) and 1.965(4) Å and trans angles of 145.1(2)° and 146.2(2)°, reflecting a distorted square-planar geometry.

    “in 3 an oxygen atom and a nitrogen atom from two ligand molecules coordinate to Cu2+. The Cu–O1 and Cu–N1 bond lengths are 1.873(4) and 1.965(4) Å, respectively, and the trans angles O1–Cu1–O1#1 and N1#1–Cu1–N1 are 145.1(2)° and 146.2(2)°, respectively, reflecting a distorted square-planar geometry for Cu2+.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    L1 shows a decrease in ThT fluorescence upon addition of nanomolar amounts, and competitive-binding curve fitting yields a Ki value of 260 ± 40 nM.

    “L1 shows a decrease in ThT fluorescence upon the addition of nanomolar amounts. Competitive-binding curve fitting yields a Ki value of 260 ± 40 nM (Figure 5b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For L1-Zn2+, the break occurs at ∼0.3 mole fraction of Zn2+, suggesting the formation of a 2:1 L1-Zn2+ complex.

    “For L1–Zn2+, the break occurs at ∼0.3 mole fraction of Zn2+, suggesting the formation of a 2:1 L1–Zn2+ complex (Figure S5 in the SI).40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

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

  • May combine two claims.

    Findingown data

    Titration of L1 with Aβ fibrils shows saturation behavior, and the data fit a one-site binding model with a Kd of 4.70 ± 0.30 μM, suggesting a moderate affinity of L1 for Aβ fibrils.

    “Titration of L1 with Aβ fibrils was performed, and a saturation behavior is observed. The data were fitted with a one-site binding model to give a Kd of 4.70 ± 0.30 μM (Figure 5a), which suggests a moderate affinity of L1 for the Aβ fibrils.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Only some morphological changes were observed even after 24 h of incubation, and a significant amount of Aβ42 aggregates were still observed by TEM.

    “Only some morphological changes were observed even after 24 h of incubation, and a significant amount of Aβ42 aggregates were still observed by TEM (Figure 8, panels 4 and 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the absence of metal ions, L1 leads to a low ThT fluorescence intensity, while L2 has a negligible effect on Aβ42 fibrillization, suggesting that L1 can inhibit fibrillization more efficiently than L2.

    “In the absence of metal ions, the presence of L1 leads to a low ThT fluorescence intensity, while L2 has a negligible effect on Aβ42 fibrillization, suggesting that L1 can inhibit fibrillization more efficiently than L2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Native gel electrophoresis/Western blotting analysis reveals high-molecular-weight soluble Aβ42 species and insoluble aggregates, although to a lesser extent in the presence of L1.

    “Native gel electrophoresis/Western blotting analysis reveals high-molecular-weight soluble Aβ42 species and insoluble aggregates, although to a lesser extent in the presence of L1 (Figure 8, lanes 4 and 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Almost no changes were observed in the spectra of both L1 and L2 upon addition of Zn2+, so the corresponding stability constants could not be determined.

    “almost no changes were observed in the spectra of both L1 and L2 upon the addition of Zn2+; therefore, the corresponding stability constants could not be determined”
    Quote in the paperNot a substantial claim

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

    Findingown data

    For L2, the best fit to the UV-vis titration data was obtained with two pKa values of 3.154(2) and 9.360(1).

    “For L2, the best fit to the data was obtained with two pKa values of 3.154(2) and 9.360(1) (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The 2:1 complex formation was confirmed by the ESI-MS signal at m/z 658.1 corresponding to [M + H]+, which was further supported by X-ray structural determination.

    “The 2:1 complex formation was confirmed by the ESI-MS signal at m/z 658.1 corresponding to [M + H]+, which was further supported by X-ray structural determination (see below).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Either L1 or L2 in metal-free conditions does not disaggregate preformed Aβ42 fibrils to an appreciable extent.

    “First, either L1 or L2 in metal-free conditions does not disaggregate the preformed Aβ42 fibrils to an appreciable extent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Spectrophotometric titration of L2 in the presence of Cu2+ revealed few spectral changes at micromolar concentrations, and higher concentrations led to precipitation of the L2-Cu2+ complex.

    “the spectrophotometric titration of L2 in the presence of Cu2+ revealed few spectral changes at micromolar concentrations, while the use of higher concentrations led to precipitation of the L2–Cu2+ complex”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Complex 3 has structural properties similar to those of 1, yet it crystallized out in the P2/n space group.

    “The copper complex 3 afforded single crystals by Et2O diffusion into a CH2Cl2 solution and has structural properties similar to those of 1, yet it crystallized out in the P2/n space group.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The UV-vis spectrum of the L1-Cu2+ complex 1 reveals a d-d transition at ∼700 nm and a more intense band at 540 nm, while a phenolate-to-Cu2+ charge-transfer band is observed at ∼400 nm.

    “The UV–vis spectrum of the L1–Cu2+ complex 1 reveals a d–d transition at ∼700 nm and a more intense band at 540 nm, while a phenolate-to-Cu2+ charge-transfer band is observed at ∼400 nm (Figure S6 in the SI).40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

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

  • May combine two claims.

    Findingown data

    For complex 2, the Zn2+ ion exhibits a distorted tetrahedral geometry and is coordinated to the benzothiazole nitrogen and phenol oxygen atoms of L1 and two chloride ions.

    “For complex 2, the Zn2+ ion exhibits a distorted tetrahedral geometry and is coordinated to the benzothiazole nitrogen and phenol oxygen atoms of L1 and two chloride ions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    L2 did not show any significant increase in fluorescence intensity in the presence of Aβ fibrils yet replaces ThT from Aβ fibrils and exhibits a Ki value of 15 ± 10 nM, indicating a very strong binding affinity to Aβ fibrils.

    “L2 did not show any significant increase in the fluorescence intensity in the presence of Aβ fibrils yet replaces ThT from the Aβ fibrils and exhibits a Ki value of 15 ± 10 nM, indicating a very strong binding affinity to Aβ fibrils (Figure 5c).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Native gel electrophoresis/Western blotting analysis supports the TEM results for Aβ40, although it is less informative because of the lack of formation of an appreciable amount of soluble Aβ oligomers under any experimental conditions.

    “The TEM results are also supported by native gel electrophoresis/Western blotting analysis (Figure S10 in the SI), although this is less informative than in the case of the Aβ42 peptide because of the lack of formation of an appreciable amount of soluble Aβ oligomers under any experimental conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Native gel/Western blotting shows that while there is a slightly increased amount of low-molecular-weight (10-80 kDa) soluble Aβ42 species, more insoluble aggregates are also observed at the top of the gel.

    “This is supported by native gel/Western blotting, which shows that while there is a slightly increased amount of low-molecular-weight (10–80 kDa) soluble Aβ42 species, more insoluble aggregates are also observed at the top of the gel (Figure 8, lanes 5 and 8).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The presence of either L1 or L2 has a dramatic effect on the Cu2+-mediated oligomerization of Aβ42 and promotes the formation of larger Aβ42 aggregates.

    “the presence of either L1 or L2 has a dramatic effect on the Cu2+-mediated oligomerization of Aβ42 and promotes the formation of larger Aβ42 aggregates, as observed by TEM (Figure 7, panels 5 and 8).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the presence of Cu2+ and either L1 or L2, a small amount of Aβ40 fibrils are still formed, while the presence of Zn2+ and either L1 or L2 leads to the formation of a larger amount of fibrillar or amorphous aggregates, respectively.

    “in the presence of Cu2+ and either L1 or L2, a small amount of Aβ40 fibrils are still formed (Figure S9 in the SI, panels 5 and 8), while the presence of Zn2+ and either L1 or L2 leads to the formation of a larger amount of fibrillar or amorphous aggregates, respectively (Figure S9 in the SI, panels 6 and 9).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The presence of either L1 or L2 in the absence of metal ions does not significantly inhibit Aβ42 aggregation, although some morphological changes were observed for the Aβ42 fibrils.

    “The presence of either L1 or L2 in the absence of metal ions does not seem to significantly inhibit Aβ42 aggregation, although some morphological changes were observed for the Aβ42 fibrils (Figure 7, panels 4 and 7)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aggregation of Aβ42 in the absence of metal ions forms high-molecular-weight oligomers, along with insoluble aggregates.

    “aggregation of Aβ42 in the absence of metal ions also forms high-molecular-weight oligomers, along with the insoluble aggregates that are observed at the top of the blot”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In complex 1, Cu2+ is coordinated by an oxygen and a nitrogen atom from two ligand molecules, with Cu-O1 and Cu-N1 bond lengths of 1.980(3) and 1.876(2) Å and trans angles of 153.3(2)° and 154.2(2)°, indicating a distorted square-planar geometry.

    “An oxygen atom and a nitrogen atom from two ligand molecules coordinate to Cu2+. The Cu–O1 and Cu–N1 bond lengths are 1.980(3) and 1.876(2) Å, respectively, and the trans angles O1–Cu1–O1#1 and N1#1–Cu1–N1 are 153.3(2)° and 154.2(2)°, respectively, with these parameters suggesting a distorted square-planar geometry for Cu2+.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the presence of Cu2+, either L1 or L2 partially inhibits the Cu2+-promoted formation of small soluble aggregates and allows for enhanced Aβ42 aggregation.

    “In the presence of Cu2+, either L1 or L2 partially inhibits the Cu2+-promoted formation of small soluble aggregates and allows for enhanced Aβ42 aggregation (Figure 8, panels 5 and 8 vs panel 2).”
    Quote in the paperSubstantial claim

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

    Findingcitation

    The UV-vis spectrum of the L2-Cu2+ complex 3 shows characteristic d-d transition bands at 700 and 515 nm as well as a phenolate-to-Cu charge-transfer band at ∼400 nm.

    “Similarly, the UV–vis spectrum of the L2–Cu2+ complex 3 shows characteristic d–d transition bands at 700 and 515 nm as well as a phenolate-to-Cu charge-transfer band at ∼400 nm (Figure S7 in the SI).40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

      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.

    Findingown data

    No Job's plot analysis could be performed for L2-Cu2+ because of the limited solubility of this complex, while no significant spectral change was observed for the L2-Zn2+ system.

    “By contrast to L1, no Job’s plot analysis could be performed for L2–Cu2+ because of the limited solubility of this complex, while no significant spectral change was observed for the L2–Zn2+ system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both L1 and L2 show no appreciable cell toxicity (>80% cell survival) even up to 20 μM concentration.

    “Both L1 and L2 show no appreciable cell toxicity (>80% cell survival) even up to 20 μM concentration.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Exley et al. showed that both sub- and superstoichiometric concentrations of Cu2+ prevent aggregation of Aβ42 into ThT-positive β-sheet-rich amyloid fibrils.

    “Exley et al. have used fluorescence assays and transmission electron microscopy (TEM) to show that both sub- and superstoichiometric concentrations of Cu2+ prevent aggregation of Aβ42 into thioflavin T (ThT)-positive β-sheet-rich amyloid fibrils.17−19”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] House, 2004, J. Alzheimer’s Dis. source
    • cites [18] Exley, 2006, J. Alzheimer’s Dis. source
    • cites [19] Exley, 2012, Coord. Chem. Rev. source

  • May combine two claims.

    Interpretationcitation

    The first and second pKa values of L1 can be assigned to deprotonation of the nitrogen atoms of the benzothiazole and diethylamino groups, while the largest pKa value is likely due to phenol deprotonation.

    “The first and second pKa values can be assigned to deprotonation of the nitrogen atoms of the benzothiazole and diethylamino groups, while the largest pKa value is likely due to phenol deprotonation.25,42”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Choi, 2010, Proc. Natl. Acad. Sci. U.S.A. source
    • cites [42] Storr, 2007, J. Am. Chem. Soc. source

  • May combine two claims.

    Premisecitation

    Copper, iron, and zinc ions affect Aβ aggregation and lead to formation of reactive oxygen species.

    “These metal ions have been shown to affect Aβ aggregation, as well as lead to the formation of reactive oxygen species (ROS).12−16”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [12] Bush, 1994, Science source
    • cites [13] Atwood, 1998, J. Biol. Chem. source
    • cites [14] Hureau, 2009, Biochimie source
    • cites [15] Zhu, 2007, Cell. Mol. Life Sci. source
    • cites [16] Crichton, 2008, Coord. Chem. Rev. source

  • May combine two claims.

    Interpretationreasoning

    L1 and L2 are expected to cross the BBB.

    “suggesting that these BFCs are expected to cross the BBB.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Unusually high concentrations of copper, iron, and zinc are found within amyloid deposits in AD-affected brains.

    “unusually high concentrations of copper, iron, and zinc have been found within the amyloid deposits in AD-affected brains.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Lovell, 1998, J. Neurol. Sci. source

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

    Interpretationown data

    The parent molecule HPB has emission properties similar to those of L2, which suggests that having a diethylamino group in L1 strongly affects its emission properties.

    “The parent molecule HPB has emission properties similar to those of L2 (Figure S4 in the SI), which suggests that having a diethylamino group in L1 strongly affects its emission properties.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40]

      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).

    Interpretationreasoning

    The lower pCu values for Cu-L1 compared to HPB are likely due to the strong electron-withdrawing effect of the diethylamine group upon protonation.

    “likely because of the strong electron-withdrawing effect of the diethylamine group upon protonation”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    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.

    “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 paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    All of these in vitro studies suggest that compounds L1 and L2 should control the formation of Cu2+-stabilized soluble Aβ42 species and thus should control their neurotoxicity.

    “Overall, all of these in vitro studies suggest that compounds L1 and L2 should control the formation of Cu2+-stabilized soluble Aβ42 species and thus should control their neurotoxicity (vide infra).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Because soluble Aβ42 oligomers are the most neurotoxic species, L1 and L2 are expected to control the neurotoxicity of Aβ42 species in the presence of metal ions.

    “Because the soluble Aβ42 oligomers are the most neurotoxic species, these compounds are expected to control the neurotoxicity of Aβ42 species in the presence of metal ions (vide infra).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Soluble Aβ42 oligomers are the most neurotoxic species.

  • May combine two claims.

    Interpretationown data

    The BFCs described herein bind to metal ions and Aβ fibrils only with moderate affinity.

    “However, the BFCs described herein bind to metal ions and Aβ fibrils only with moderate affinity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cu2+ by itself is not toxic to N2A cells, but the presence of Cu2+ and either monomeric Aβ42 or soluble Aβ42 oligomers exhibits enhanced cell toxicity.

    “while Cu2+ by itself is not toxic to N2A cells, the presence of Cu2+ and either monomeric Aβ42 or soluble Aβ42 oligomers exhibits enhanced cell toxicity.17,18”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] House, 2004, J. Alzheimer’s Dis. source
    • cites [18] Exley, 2006, J. Alzheimer’s Dis. source
63 of 63

  • The paper relies on this without support.

    ThT is well-known for its amyloid-binding properties because of the 2-phenylbenzothiazole aromatic framework.

    “The fluorescent dye ThT is well-known for its amyloid-binding properties because of the 2-phenylbenzothiazole aromatic framework.”

  • The paper relies on this without support.

    The molecular mechanisms of metal–Aβ species interactions, especially for the more neurotoxic Aβ42, are still not completely understood.

    “Although many studies have investigated the involvement of metal ions in Aβ aggregation and plaque formation, the molecular mechanisms of metal–Aβ species interactions, especially for the more neurotoxic Aβ42, are still not completely understood.”

  • The paper relies on this without support.

    Specific rather than systemic metal chelation by these compounds is needed to limit side effects.

    “However, specific rather than systemic metal chelation by these compounds is needed in order to limit any side effects.”

  • The paper relies on this without support.

    Soluble Aβ42 oligomers are the most neurotoxic species.

    “Because the soluble Aβ42 oligomers are the most neurotoxic species”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conclusion calls L2's fibril affinity moderate despite reporting very strong binding

    Major

    The conclusion characterizes both compounds' affinity for Aβ fibrils as only moderate, while the results explicitly characterize L2's measured 15 nM affinity as very strong.

  • ThT competition assay concentrations differ

    Minor

    The methods specify 5 μM Aβ fibrils and 2 μM ThT, but the Figure 5 caption specifies 2 μM Aβ and 1 μM ThT for the competition assays.

  • Inhibition experiment is described as treating preformed fibrils

    Minor

    The results section says the inhibition experiments treated freshly prepared fibrils, but the methods distinguish adding compounds to Aβ solutions for inhibition from treating preformed fibrils for disaggregation.

  • Copper-treated oligomer results cite the metal-free lanes

    Minor

    The text cites Figure 9 lanes 9 and 10 for the effect in the presence of Cu2+, but the caption assigns those lanes to metal-free oligomers with L1 and L2. The Cu2+-containing counterparts are lanes 11 and 12.

  • Zinc-complex synthesis names the wrong ligand

    Minor

    The procedure for the L1 zinc complex says it uses L4, whereas the product heading and reported mass spectrum identify the ligand as L1.

  • Cu-N and Cu-O bond lengths are reversed

    Minor

    For complex 1, the text assigns 1.980 Å to Cu-O and 1.876 Å to Cu-N; the Figure 4 caption assigns those same lengths to Cu-N and Cu-O, respectively.

6 of 6

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 (2014-10-21).

    Cited work 10.1038/nature04533 · retracted 2024-06-24 · notice 10.1038/s41586-024-07691-8 · this paper published 2014-10-21

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. Braymer, 2011, Int. J. Alzheimer’s Dis., 2011, 623051, 10.4061/2011/623051 · DOI · Paper page
  2. Gans, 1999, Ann. Chim., 45
  3. Haass, 2007, Nat. Rev. Mol. Cell Biol., 8, 101, 10.1038/nrm2101 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Sharma, A. K., Kim, J., Prior, J. T., Hawco, N. J., Rath, N. P., Kim, J., & Mirica, L. M.
Affiliations
  • Washington University in St. Louis (US)
  • University of Missouri–St. Louis (US)
Corresponding author
Mirica, Liviu M.
ORCID
Venue
Inorganic Chemistry
Publisher
American Chemical Society (ACS)
Published
2014-10-21
Volume
53
Issue
21
Pages
11367-11376
ISSN
  • 0020-1669 (ISSN-L)
  • 1520-510X
DOI
10.1021/ic500926c
PMC
PMC4220862
OpenAlex
W2330115237
Semantic Scholar
630983fd049ae2608e213d551f53ffd8b361e8fa
Cited by
48
References
51
Citations by year
2026: 2 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 9 · 2019: 2 · 2018: 3 · 2017: 9 · 2016: 6 · 2015: 3
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Inorganic Chemistry (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Institute on Aging (NIH P50-AG05681)
  • National Institute of Neurological Disorders and Stroke (NIH P30NS69329)
  • Alfred P. Sloan Foundation (NA)
  • Alzheimer's Association (NIRP-12-259199)
  • Oak Ridge Associated Universities (NA)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
Keywords
amyloid-beta, Alzheimer's disease, benzothiazole ligands, thioflavin T, Aβ42 oligomers, metal complex stability constants, amyloid fibril binding
MeSH terms
Animals, Cell Survival, Chelating Agents, Clioquinol, Models, Molecular, Molecular Structure, Amyloid beta-Peptides, Crystallography, X-Ray, Cell Line, Tumor, Mice, Protein Aggregation, Pathological, Protein Aggregates

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.

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Statistics and arithmetic are recomputed, not judged.

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