Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation
Amyloid-β (Aβ) is a peptide formed by 39–43 amino acids, heterogenous by the length of its C-terminus. Aβ constitutes a subnanomolar monomeric component of human biological fluids; however, in sporadic variants of Alzheimer’s disease (AD), it forms soluble neurotoxic oligomers and accumulates as ins...
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2023-07-01
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| author | Olga I. Kechko Alexei A. Adzhubei Anna P. Tolstova Maria I. Indeykina Igor A. Popov Sergey S. Zhokhov Nikolay V. Gnuchev Vladimir A. Mitkevich Alexander A. Makarov Sergey A. Kozin |
| author_facet | Olga I. Kechko Alexei A. Adzhubei Anna P. Tolstova Maria I. Indeykina Igor A. Popov Sergey S. Zhokhov Nikolay V. Gnuchev Vladimir A. Mitkevich Alexander A. Makarov Sergey A. Kozin |
| author_sort | Olga I. Kechko |
| collection | DOAJ |
| description | Amyloid-β (Aβ) is a peptide formed by 39–43 amino acids, heterogenous by the length of its C-terminus. Aβ constitutes a subnanomolar monomeric component of human biological fluids; however, in sporadic variants of Alzheimer’s disease (AD), it forms soluble neurotoxic oligomers and accumulates as insoluble extracellular polymeric aggregates (amyloid plaques) in the brain tissues. The plaque formation is controlled by zinc ions; therefore, abnormal interactions between the ions and Aβ seem to take part in the triggering of sporadic AD. The amyloid plaques contain various Aβ isoforms, among which the most common is Aβ with an isoaspartate in position 7 (isoD7). The spontaneous conversion of D7 to isoD7 is associated with Aβ aging. Aβ molecules with isoD7 (isoD7-Aβ) easily undergo zinc-dependent oligomerization, and upon administration to transgenic animals (mice, nematodes) used for AD modeling, act as zinc-dependent seeds of the pathological aggregation of Aβ. The formation of zinc-bound homo- and hetero-oligomers with the participation of isoD7-Aβ is based on the rigidly structured segment 11-EVHH-14, located in the Aβ metal binding domain (Aβ<sub>16</sub>). Some hereditary variants of AD are associated with familial mutations within the domain. Among these, the most susceptible to zinc-dependent oligomerization is Aβ with Taiwan (D7H) mutation (D7H-Aβ). In this study, the D7H-Aβ metal binding domain (D7H-Aβ<sub>16</sub>) has been used as a model to establish the molecular mechanism of zinc-induced D7H-Aβ oligomerization through turbidimetry, dynamic light scattering, isothermal titration calorimetry, mass spectrometry, and computer modelling. Additionally, the modeling data showed that a molecule of D7H-Aβ, as well as isoD7-Aβ in combination with two Aβ molecules, renders a stable zinc-induced heterotrimer. The trimers are held together by intermolecular interfaces via zinc ions, with the primary interfaces formed by 11-EVHH-14 sites of the interacting trimer subunits. In summary, the obtained results confirm the role of the 11-EVHH-14 region as a structure and function determinant for the zinc-dependent oligomerization of all known Aβ species (including various chemically modified isoforms and AD-associated mutants) and point at this region as a potent target for drugs aimed to stop amyloid plaque formation in both sporadic and hereditary variants of AD. |
| first_indexed | 2024-03-11T01:01:32Z |
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| issn | 1661-6596 1422-0067 |
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| last_indexed | 2024-03-11T01:01:32Z |
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| spelling | doaj.art-4d6386aa964f45b59208cce36f5716212023-11-18T19:36:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141124110.3390/ijms241411241Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) MutationOlga I. Kechko0Alexei A. Adzhubei1Anna P. Tolstova2Maria I. Indeykina3Igor A. Popov4Sergey S. Zhokhov5Nikolay V. Gnuchev6Vladimir A. Mitkevich7Alexander A. Makarov8Sergey A. Kozin9Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaMoscow Institute of Physics and Technology, 141701 Dolgoprudny, RussiaDepartment of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, RussiaAmyloid-β (Aβ) is a peptide formed by 39–43 amino acids, heterogenous by the length of its C-terminus. Aβ constitutes a subnanomolar monomeric component of human biological fluids; however, in sporadic variants of Alzheimer’s disease (AD), it forms soluble neurotoxic oligomers and accumulates as insoluble extracellular polymeric aggregates (amyloid plaques) in the brain tissues. The plaque formation is controlled by zinc ions; therefore, abnormal interactions between the ions and Aβ seem to take part in the triggering of sporadic AD. The amyloid plaques contain various Aβ isoforms, among which the most common is Aβ with an isoaspartate in position 7 (isoD7). The spontaneous conversion of D7 to isoD7 is associated with Aβ aging. Aβ molecules with isoD7 (isoD7-Aβ) easily undergo zinc-dependent oligomerization, and upon administration to transgenic animals (mice, nematodes) used for AD modeling, act as zinc-dependent seeds of the pathological aggregation of Aβ. The formation of zinc-bound homo- and hetero-oligomers with the participation of isoD7-Aβ is based on the rigidly structured segment 11-EVHH-14, located in the Aβ metal binding domain (Aβ<sub>16</sub>). Some hereditary variants of AD are associated with familial mutations within the domain. Among these, the most susceptible to zinc-dependent oligomerization is Aβ with Taiwan (D7H) mutation (D7H-Aβ). In this study, the D7H-Aβ metal binding domain (D7H-Aβ<sub>16</sub>) has been used as a model to establish the molecular mechanism of zinc-induced D7H-Aβ oligomerization through turbidimetry, dynamic light scattering, isothermal titration calorimetry, mass spectrometry, and computer modelling. Additionally, the modeling data showed that a molecule of D7H-Aβ, as well as isoD7-Aβ in combination with two Aβ molecules, renders a stable zinc-induced heterotrimer. The trimers are held together by intermolecular interfaces via zinc ions, with the primary interfaces formed by 11-EVHH-14 sites of the interacting trimer subunits. In summary, the obtained results confirm the role of the 11-EVHH-14 region as a structure and function determinant for the zinc-dependent oligomerization of all known Aβ species (including various chemically modified isoforms and AD-associated mutants) and point at this region as a potent target for drugs aimed to stop amyloid plaque formation in both sporadic and hereditary variants of AD.https://www.mdpi.com/1422-0067/24/14/11241Alzheimer’s diseaseamyloid-betafamilial Taiwan mutation D7Hzincmetal binding domainoligomerization |
| spellingShingle | Olga I. Kechko Alexei A. Adzhubei Anna P. Tolstova Maria I. Indeykina Igor A. Popov Sergey S. Zhokhov Nikolay V. Gnuchev Vladimir A. Mitkevich Alexander A. Makarov Sergey A. Kozin Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation International Journal of Molecular Sciences Alzheimer’s disease amyloid-beta familial Taiwan mutation D7H zinc metal binding domain oligomerization |
| title | Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation |
| title_full | Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation |
| title_fullStr | Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation |
| title_full_unstemmed | Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation |
| title_short | Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation |
| title_sort | molecular mechanism of zinc dependent oligomerization of alzheimer s amyloid β with taiwan d7h mutation |
| topic | Alzheimer’s disease amyloid-beta familial Taiwan mutation D7H zinc metal binding domain oligomerization |
| url | https://www.mdpi.com/1422-0067/24/14/11241 |
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