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Conformation pattern changes in R1-pS262 tau peptide induced endogenous tau aggregation, synaptic damage, and cognitive impairments.

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Title: Conformation pattern changes in R1-pS262 tau peptide induced endogenous tau aggregation, synaptic damage, and cognitive impairments.
Authors: Wu, Gang1,2 (AUTHOR), Luo, Yong1,2 (AUTHOR), Guo, Qian1 (AUTHOR), Yang, Mingming1 (AUTHOR), Mahaman, Yacoubou Abdoul Razak3 (AUTHOR), Liu, Yi1 (AUTHOR), Wang, Jian-Zhi1,2,4 (AUTHOR), Liu, Rong1 (AUTHOR), Gao, Xiang5 (AUTHOR) gaoyangxixi@whu.edu.cn, Wang, Xiaochuan1,2,4 (AUTHOR) wxch@mails.tjmu.edu.cn
Source: Journal of Alzheimer's Disease. Feb2025, Vol. 103 Issue 3, p951-965. 15p.
Subject Terms: *PROTEIN structure prediction, *PEPTIDE mass fingerprinting, *CONFORMATIONAL analysis, *ALZHEIMER'S disease, *PROTEIN conformation, *TAU proteins
Abstract: Background: To date, the effect of tau phosphorylation at different amino acid sites on the conformation and function of tau is still unclear in Alzheimer's disease (AD). Protein fingerprinting, also known as the protein folding shape code (PFSC) method, is a protein structure prediction technique based on protein sequence, which can reveal proteins' most likely spatial conformation. Objective: To investigate the effect of phosphorylation on tau protein conformation using PFSC technology and further analyze the differences in the effect of phosphorylation on tau aggregation at specific sites. Methods: We performed a conformational analysis of wild-type and simulated mutant hTau441 using the PFSC method and synthesized the phosphorylated and non-phosphorylated tau fragments by the chemical solid phase method. Results: We found that the number of Ser262 protein fingerprints increased from six in tau S262A to nine in tau S262E, together with increased conformational changes and enhanced flexibility. The in vitro Thioflavin S assay showed that phosphorylated tau fragments R1-pS262 possessed a stronger activity of inducing tau aggregation. In contrast to the non-phosphorylated tau fragment R1-nS262, R1-pS262 promoted endogenous tau aggregation and decreased synaptic proteins. In rats, R1-pS262 caused cognitive impairments and neuronal loss in addition to endogenous tau aggregation and synaptic damage. Conclusions: Our study firstly reports that tau phosphorylation at Ser262 induces tau aggregation, and phosphorylated tau fragments R1-pS262 directly result in neuropathological changes. These provide new clues to the pathogenesis of tauopathy, such as AD, and a new molecular target for possible intervention. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Alzheimer's Disease is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
  Group: Ti
  Data: Conformation pattern changes in R1-pS262 tau peptide induced endogenous tau aggregation, synaptic damage, and cognitive impairments.
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  Data: <searchLink fieldCode="AR" term="%22Wu%2C+Gang%22">Wu, Gang</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Luo%2C+Yong%22">Luo, Yong</searchLink><relatesTo>1,2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Guo%2C+Qian%22">Guo, Qian</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yang%2C+Mingming%22">Yang, Mingming</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mahaman%2C+Yacoubou+Abdoul+Razak%22">Mahaman, Yacoubou Abdoul Razak</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Yi%22">Liu, Yi</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Jian-Zhi%22">Wang, Jian-Zhi</searchLink><relatesTo>1,2,4</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Liu%2C+Rong%22">Liu, Rong</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gao%2C+Xiang%22">Gao, Xiang</searchLink><relatesTo>5</relatesTo> (AUTHOR)<i> gaoyangxixi@whu.edu.cn</i><br /><searchLink fieldCode="AR" term="%22Wang%2C+Xiaochuan%22">Wang, Xiaochuan</searchLink><relatesTo>1,2,4</relatesTo> (AUTHOR)<i> wxch@mails.tjmu.edu.cn</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Alzheimer's+Disease%22">Journal of Alzheimer's Disease</searchLink>. Feb2025, Vol. 103 Issue 3, p951-965. 15p.
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: *<searchLink fieldCode="DE" term="%22PROTEIN+structure+prediction%22">PROTEIN structure prediction</searchLink><br />*<searchLink fieldCode="DE" term="%22PEPTIDE+mass+fingerprinting%22">PEPTIDE mass fingerprinting</searchLink><br />*<searchLink fieldCode="DE" term="%22CONFORMATIONAL+analysis%22">CONFORMATIONAL analysis</searchLink><br />*<searchLink fieldCode="DE" term="%22ALZHEIMER'S+disease%22">ALZHEIMER'S disease</searchLink><br />*<searchLink fieldCode="DE" term="%22PROTEIN+conformation%22">PROTEIN conformation</searchLink><br />*<searchLink fieldCode="DE" term="%22TAU+proteins%22">TAU proteins</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Background: To date, the effect of tau phosphorylation at different amino acid sites on the conformation and function of tau is still unclear in Alzheimer's disease (AD). Protein fingerprinting, also known as the protein folding shape code (PFSC) method, is a protein structure prediction technique based on protein sequence, which can reveal proteins' most likely spatial conformation. Objective: To investigate the effect of phosphorylation on tau protein conformation using PFSC technology and further analyze the differences in the effect of phosphorylation on tau aggregation at specific sites. Methods: We performed a conformational analysis of wild-type and simulated mutant hTau441 using the PFSC method and synthesized the phosphorylated and non-phosphorylated tau fragments by the chemical solid phase method. Results: We found that the number of Ser262 protein fingerprints increased from six in tau S262A to nine in tau S262E, together with increased conformational changes and enhanced flexibility. The in vitro Thioflavin S assay showed that phosphorylated tau fragments R1-pS262 possessed a stronger activity of inducing tau aggregation. In contrast to the non-phosphorylated tau fragment R1-nS262, R1-pS262 promoted endogenous tau aggregation and decreased synaptic proteins. In rats, R1-pS262 caused cognitive impairments and neuronal loss in addition to endogenous tau aggregation and synaptic damage. Conclusions: Our study firstly reports that tau phosphorylation at Ser262 induces tau aggregation, and phosphorylated tau fragments R1-pS262 directly result in neuropathological changes. These provide new clues to the pathogenesis of tauopathy, such as AD, and a new molecular target for possible intervention. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Alzheimer's Disease is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1177/13872877241307341
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      – Code: eng
        Text: English
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        PageCount: 15
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      – SubjectFull: PROTEIN structure prediction
        Type: general
      – SubjectFull: PEPTIDE mass fingerprinting
        Type: general
      – SubjectFull: CONFORMATIONAL analysis
        Type: general
      – SubjectFull: ALZHEIMER'S disease
        Type: general
      – SubjectFull: PROTEIN conformation
        Type: general
      – SubjectFull: TAU proteins
        Type: general
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      – TitleFull: Conformation pattern changes in R1-pS262 tau peptide induced endogenous tau aggregation, synaptic damage, and cognitive impairments.
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              Text: Feb2025
              Type: published
              Y: 2025
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