Zn2+ Aggravates Tau Aggregation and Neurotoxicity

Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons....

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Published inInternational journal of molecular sciences Vol. 20; no. 3; p. 487
Main Authors Li, Xuexia, Du, Xiubo, Ni, Jiazuan
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 23.01.2019
MDPI
Subjects
Binding sites
Brain
Homeostasis
Nervous system
Neurotoxicity
Pathogenesis
Peptides
Physiology
Proteins
Online AccessGet full text
ISSN1422-0067
1661-6596
1422-0067
DOI10.3390/ijms20030487

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Abstract Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+ is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+ on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+ via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 104 M−1). Zn2+ accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+ can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+ dyshomeostasis and the etiology of Alzheimer’s disease.
AbstractList Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn 2+ is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn 2+ on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn 2+ via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 10 4 M −1 ). Zn 2+ accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn 2+ -tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn 2+ -tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn 2+ -tau-R3 aggregates were found to be taken up by N2A cells, and more Zn 2+ -tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn 2+ can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn 2+ dyshomeostasis and the etiology of Alzheimer’s disease.
The abnormal aggregation of tau proteins forms insoluble paired helix filaments (PHF) that cause nerve fiber tangles, which are one of the main pathological features of AD. [...]the molecular mechanism of the abnormal aggregation of tau protein has become the key to the study of AD pathology. Sun et al. found that synaptically released Zn2+ promoted tau hyperphosphorylation through protein phosphatase 2A (PP2A) inhibition [28]. [...]abnormal Zn2+ homeostasis is believed to be a contributing factor leading to tau aggregation, and the alteration of Zn2+ homeostasis is a potential therapeutic strategy for AD. [...]levels of manganese, molybdenum, and iron were also changed significantly among Alzheimer disease, mild cognitive impairment, subjective memory complaint, and healthy subjects [29]. [...]in the present study, by using isothermal titration calorimetry (ITC) and UV-vis spectroscopy, the thermodynamic properties of tau-R3 binding Mn2+, Mo5+, Fe3+, and Zn2+ were characterized. The ΔH and ΔS were estimated to be −16.58 ± 0.33 kcal mol−1 and −33.5 cal/mol/deg, respectively. [...]the binding of Zn2+ to tau-R3 is an entropy-driven, but not enthalpy-driven reaction.
Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+ is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+ on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+ via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 104 M−1). Zn2+ accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+ can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+ dyshomeostasis and the etiology of Alzheimer’s disease.
Alzheimer's disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+ is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+ on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+ via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 10⁴ M-1). Zn2+ accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+ can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+ dyshomeostasis and the etiology of Alzheimer's disease.Alzheimer's disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+ is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+ on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+ via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 10⁴ M-1). Zn2+ accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+ can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+ dyshomeostasis and the etiology of Alzheimer's disease.
Author Li, Xuexia
Du, Xiubo
Ni, Jiazuan
AuthorAffiliation 1 Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; xxli@ciac.ac.cn
3 College of Life Sciences and Oceanography, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen 518060, China
2 School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China
AuthorAffiliation_xml – name: 3 College of Life Sciences and Oceanography, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen 518060, China
– name: 1 Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China; xxli@ciac.ac.cn
– name: 2 School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China
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  givenname: Jiazuan
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Snippet Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been...
The abnormal aggregation of tau proteins forms insoluble paired helix filaments (PHF) that cause nerve fiber tangles, which are one of the main pathological...
Alzheimer's disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been...
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StartPage 487
SubjectTerms Binding sites
Brain
Homeostasis
Nervous system
Neurotoxicity
Pathogenesis
Peptides
Physiology
Proteins
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Title Zn2+ Aggravates Tau Aggregation and Neurotoxicity
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