Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition
The triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a pote...
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2018.00302/full |
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| author | Evgeny P. Barykin Irina Y. Petrushanko Sergey A. Kozin Georgy B. Telegin Alexander S. Chernov Olga D. Lopina Sergey P. Radko Vladimir A. Mitkevich Alexander A. Makarov |
| author_facet | Evgeny P. Barykin Irina Y. Petrushanko Sergey A. Kozin Georgy B. Telegin Alexander S. Chernov Olga D. Lopina Sergey P. Radko Vladimir A. Mitkevich Alexander A. Makarov |
| author_sort | Evgeny P. Barykin |
| collection | DOAJ |
| description | The triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aβ, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aβ are neutralized by its phosphorylation. |
| first_indexed | 2024-12-12T14:20:57Z |
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| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-12T14:20:57Z |
| publishDate | 2018-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-9d05c2f30fda491cb02821a30efaacfd2022-12-22T00:21:48ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992018-08-011110.3389/fnmol.2018.00302373299Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque DepositionEvgeny P. Barykin0Irina Y. Petrushanko1Sergey A. Kozin2Georgy B. Telegin3Alexander S. Chernov4Olga D. Lopina5Sergey P. Radko6Vladimir A. Mitkevich7Alexander A. Makarov8Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, RussiaPushchino Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino, RussiaPushchino Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Pushchino, RussiaFaculty of Biology, Lomonosov Moscow State University, Moscow, RussiaInstitute of Biomedical Chemistry, Russian Academy of Sciences, Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, RussiaEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, RussiaThe triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aβ, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aβ are neutralized by its phosphorylation.https://www.frontiersin.org/article/10.3389/fnmol.2018.00302/fullAlzheimer’s diseaseβ-amyloidNa+K+-ATPasezincprotein phosphorylation |
| spellingShingle | Evgeny P. Barykin Irina Y. Petrushanko Sergey A. Kozin Georgy B. Telegin Alexander S. Chernov Olga D. Lopina Sergey P. Radko Vladimir A. Mitkevich Alexander A. Makarov Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition Frontiers in Molecular Neuroscience Alzheimer’s disease β-amyloid Na+ K+-ATPase zinc protein phosphorylation |
| title | Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition |
| title_full | Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition |
| title_fullStr | Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition |
| title_full_unstemmed | Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition |
| title_short | Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition |
| title_sort | phosphorylation of the amyloid beta peptide inhibits zinc dependent aggregation prevents na k atpase inhibition and reduces cerebral plaque deposition |
| topic | Alzheimer’s disease β-amyloid Na+ K+-ATPase zinc protein phosphorylation |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2018.00302/full |
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