Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain

Youssra K Al-Hilaly; Bronwen E Foster; Luca Biasetti; Liisa Lutter; Saskia J Pollack; Janet E Rickard; John M D Storey; Charles R Harrington; Wei-Feng Xue; Claude M Wischik; Louise C Serpell

doi:10.1002/1873-3468.13675

Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain

Youssra K Al-Hilaly^* (Corresponding Author), Bronwen E Foster, Luca Biasetti, Liisa Lutter, Saskia J Pollack, Janet E Rickard, John M D Storey, Charles R Harrington, Wei-Feng Xue, Claude M Wischik, Louise C Serpell

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation.

Original language	English
Pages (from-to)	944-950
Number of pages	7
Journal	FEBS LETTERS
Volume	594
Issue number	5
Early online date	1 Dec 2019
DOIs	https://doi.org/10.1002/1873-3468.13675
Publication status	Published - 1 Mar 2020

Bibliographical note

Acknowledgements
We acknowledge Biochemical society for funding forBF. YA acknowledges Mustansiriyah University,Baghdad, Iraq (www.uomustansiriyah.edu.iq), for sup-port. We thank Pascale Schellenberger for valuablehelp and training with TEM. The human tissue wasprovided by the London Neurodegenerative DiseasesBrain Bank. Respectfully, we thank the anonymoustissue donors and their next of kin. We thank fundingfrom the BBSRC (BB/S003312/1, WFX and LCS) andthe EPSRC (EP/R513246/1, LL).Author contributionsYA managed the project, conceived the idea and pre-pared the samples. YA and BF collected and analysedthe TEM data; LB provided training and sectioned thebrain sample; YA, LL and WFX collected the AFMdata; and LL and WFX analysed the AFM data. JERprepared the purified dGAE protein. YA, BF and LSwrote the first draft and all authors reviewed themanuscript and approved the final version. CH, CWand LS managed the overall project.

Ethics
AD brain tissue was provided by the London Neu-rodegenerative Diseases Brain Bank, Institute of Psy-chiatry, King’s College, London, under Local EthicsCommittee guidelines, and informed consent for braindonation was obtained from the next of kin by theLondon Neurodegenerative Diseases Brain Bank.

Keywords

Alzheimer’s disease
neurofibrillary tangles
paired helical filaments
tau

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AlHilaly_etal_FEBS_VOR
© 2019 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/
Final published version, 1.07 MBLicence: CC BY

Cite this

Al-Hilaly, Y. K., Foster, B. E., Biasetti, L., Lutter, L., Pollack, S. J., Rickard, J. E., Storey, J. M. D., Harrington, C. R., Xue, W.-F., Wischik, C. M., & Serpell, L. C. (2020). Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain. FEBS LETTERS, 594(5), 944-950. https://doi.org/10.1002/1873-3468.13675

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abstract = "The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation.",

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author = "Al-Hilaly, {Youssra K} and Foster, {Bronwen E} and Luca Biasetti and Liisa Lutter and Pollack, {Saskia J} and Rickard, {Janet E} and Storey, {John M D} and Harrington, {Charles R} and Wei-Feng Xue and Wischik, {Claude M} and Serpell, {Louise C}",

note = "Acknowledgements We acknowledge Biochemical society for funding forBF. YA acknowledges Mustansiriyah University,Baghdad, Iraq (www.uomustansiriyah.edu.iq), for sup-port. We thank Pascale Schellenberger for valuablehelp and training with TEM. The human tissue wasprovided by the London Neurodegenerative DiseasesBrain Bank. Respectfully, we thank the anonymoustissue donors and their next of kin. We thank fundingfrom the BBSRC (BB/S003312/1, WFX and LCS) andthe EPSRC (EP/R513246/1, LL).Author contributionsYA managed the project, conceived the idea and pre-pared the samples. YA and BF collected and analysedthe TEM data; LB provided training and sectioned thebrain sample; YA, LL and WFX collected the AFMdata; and LL and WFX analysed the AFM data. JERprepared the purified dGAE protein. YA, BF and LSwrote the first draft and all authors reviewed themanuscript and approved the final version. CH, CWand LS managed the overall project. Ethics AD brain tissue was provided by the London Neu-rodegenerative Diseases Brain Bank, Institute of Psy-chiatry, King{\textquoteright}s College, London, under Local EthicsCommittee guidelines, and informed consent for braindonation was obtained from the next of kin by theLondon Neurodegenerative Diseases Brain Bank.",

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AU - Al-Hilaly, Youssra K

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AU - Biasetti, Luca

AU - Lutter, Liisa

AU - Pollack, Saskia J

AU - Rickard, Janet E

AU - Storey, John M D

AU - Harrington, Charles R

AU - Xue, Wei-Feng

AU - Wischik, Claude M

AU - Serpell, Louise C

N1 - Acknowledgements We acknowledge Biochemical society for funding forBF. YA acknowledges Mustansiriyah University,Baghdad, Iraq (www.uomustansiriyah.edu.iq), for sup-port. We thank Pascale Schellenberger for valuablehelp and training with TEM. The human tissue wasprovided by the London Neurodegenerative DiseasesBrain Bank. Respectfully, we thank the anonymoustissue donors and their next of kin. We thank fundingfrom the BBSRC (BB/S003312/1, WFX and LCS) andthe EPSRC (EP/R513246/1, LL).Author contributionsYA managed the project, conceived the idea and pre-pared the samples. YA and BF collected and analysedthe TEM data; LB provided training and sectioned thebrain sample; YA, LL and WFX collected the AFMdata; and LL and WFX analysed the AFM data. JERprepared the purified dGAE protein. YA, BF and LSwrote the first draft and all authors reviewed themanuscript and approved the final version. CH, CWand LS managed the overall project. Ethics AD brain tissue was provided by the London Neu-rodegenerative Diseases Brain Bank, Institute of Psy-chiatry, King’s College, London, under Local EthicsCommittee guidelines, and informed consent for braindonation was obtained from the next of kin by theLondon Neurodegenerative Diseases Brain Bank.

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N2 - The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation.

AB - The constituent paired helical filaments (PHFs) in neurofibrillary tangles are insoluble intracellular deposits central to the development of Alzheimer's disease (AD) and other tauopathies. Full-length tau requires the addition of anionic cofactors such as heparin to enhance assembly. We have shown that a fragment from the proteolytically stable core of the PHF, tau 297-391 known as 'dGAE', spontaneously forms cross-β-containing PHFs and straight filaments under physiological conditions. Here, we have analysed and compared the structures of the filaments formed by dGAE in vitro with those deposited in the brains of individuals diagnosed with AD. We show that dGAE forms PHFs that share a macromolecular structure similar to those found in brain tissue. Thus, dGAEs may serve as a model system for studying core domain assembly and for screening for inhibitors of tau aggregation.

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Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain

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Charles Harrington

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Tau (297-391) forms filaments that structurally mimic the core of paired helical filaments in Alzheimer's disease brain

Abstract

Bibliographical note

Keywords

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Charles Harrington

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