Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies

Frederique J. Hart de Ruyter; Tjado H.J. Morrema; Jurre den Haan; Jos W.R. Twisk; Johannes F. de Boer; Philip Scheltens; Baayla D.C. Boon; Dietmar R. Thal; Annemieke J. Rozemuller; Frank D. Verbraak; Femke H. Bouwman; Jeroen J.M. Hoozemans

doi:10.1007/s00401-022-02525-1

Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies

Frederique J. Hart de Ruyter^*, Tjado H.J. Morrema, Jurre den Haan, , Jos W.R. Twisk, Johannes F. de Boer, Philip Scheltens, Baayla D.C. Boon, Dietmar R. Thal, Annemieke J. Rozemuller, Frank D. Verbraak, Femke H. Bouwman, Jeroen J.M. Hoozemans

^*Bijbehorende auteur voor dit werk

NIN

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The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer’s disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.

Originele taal-2	Engels
Pagina's (van-tot)	197-218
Tijdschrift	Acta Neuropathologica
Volume	145
DOI's	https://doi.org/10.1007/s00401-022-02525-1
Status	Gepubliceerd - jan. 2023

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Hart de Ruyter, F. J., Morrema, T. H. J., den Haan, J., Twisk, J. W. R., de Boer, J. F., Scheltens, P., Boon, B. D. C., Thal, D. R., Rozemuller, A. J., Verbraak, F. D., & Bouwman, F. H., & Hoozemans, J. J. M. (2023). Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies. Acta Neuropathologica, 145, 197-218. https://doi.org/10.1007/s00401-022-02525-1

@article{45673c1de143458a9165d1845a4d3b4b,

title = "Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer{\textquoteright}s disease and primary tauopathies",

abstract = "The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer{\textquoteright}s disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.",

keywords = "Alzheimer{\textquoteright}s disease, Eye, Neurodegeneration, Phosphorylation, Post-mortem, Retina, Tau, Tauopathies",

author = "{Hart de Ruyter}, {Frederique J.} and Morrema, {Tjado H.J.} and {den Haan}, Jurre and Twisk, {Jos W.R.} and {de Boer}, {Johannes F.} and Philip Scheltens and Boon, {Baayla D.C.} and Thal, {Dietmar R.} and Rozemuller, {Annemieke J.} and Verbraak, {Frank D.} and Bouwman, {Femke H.} and Hoozemans, {Jeroen J.M.}",

note = "Funding Information: This research was funded by the Netherlands Organisation for Scientific Research (NWO, MEDPHOT P18-26 Project 5). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2023",

month = jan,

doi = "10.1007/s00401-022-02525-1",

language = "English",

volume = "145",

pages = "197--218",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer Verlag GmbH",

}

Hart de Ruyter, FJ, Morrema, THJ, den Haan, J, Twisk, JWR, de Boer, JF, Scheltens, P, Boon, BDC, Thal, DR, Rozemuller, AJ, Verbraak, FD & Bouwman, FH & Hoozemans, JJM 2023, 'Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies', Acta Neuropathologica, vol. 145, blz. 197-218. https://doi.org/10.1007/s00401-022-02525-1

Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies. / Hart de Ruyter, Frederique J.; Morrema, Tjado H.J.; den Haan, Jurre et al.
In: Acta Neuropathologica, Vol. 145, 01.2023, blz. 197-218.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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T1 - Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies

AU - Hart de Ruyter, Frederique J.

AU - Morrema, Tjado H.J.

AU - den Haan, Jurre

AU - Twisk, Jos W.R.

AU - de Boer, Johannes F.

AU - Scheltens, Philip

AU - Boon, Baayla D.C.

AU - Thal, Dietmar R.

AU - Rozemuller, Annemieke J.

AU - Verbraak, Frank D.

AU - Bouwman, Femke H.

AU - Hoozemans, Jeroen J.M.

N1 - Funding Information: This research was funded by the Netherlands Organisation for Scientific Research (NWO, MEDPHOT P18-26 Project 5). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2023/1

Y1 - 2023/1

N2 - The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer’s disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.

AB - The retina is a potential source of biomarkers for the detection of neurodegenerative diseases. Accumulation of phosphorylated tau (p-tau) in the brain is a pathological feature characteristic for Alzheimer’s disease (AD) and primary tauopathies. In this study the presence of p-tau in the retina in relation to tau pathology in the brain was assessed. Post-mortem eyes and brains were collected through the Netherlands Brain Bank from donors with AD (n = 17), primary tauopathies (n = 8), α-synucleinopathies (n = 13), other neurodegenerative diseases including non-tau frontotemporal lobar degeneration (FTLD) (n = 9), and controls (n = 15). Retina cross-sections were assessed by immunohistochemistry using antibodies directed against total tau (HT7), 3R and 4R tau isoforms (RD3, RD4), and phospho-epitopes Ser202/Thr205 (AT8), Thr217 (anti-T217), Thr212/Ser214 (AT100), Thr181 (AT270), Ser396 (anti-pS396) and Ser422 (anti-pS422). Retinal tau load was compared to p-tau Ser202/Thr205 and p-tau Thr217 load in various brain regions. Total tau, 3R and 4R tau isoforms were most prominently present in the inner plexiform layer (IPL) and outer plexiform layer (OPL) of the retina and were detected in all cases and controls as a diffuse and somatodendritic signal. Total tau, p-tau Ser202/Thr205 and p-tau Thr217 was observed in amacrine and horizontal cells of the inner nuclear layer (INL). Various antibodies directed against phospho-epitopes of tau showed immunoreactivity in the IPL, OPL, and INL. P-tau Ser202/Thr205 and Thr217 showed significant discrimination between AD and other tauopathies, and non-tauopathy cases including controls. Whilst immunopositivity was observed for p-tau Thr212/Ser214, Thr181 and Ser396, there were no group differences. P-tau Ser422 did not show any immunoreactivity in the retina. The presence of retinal p-tau Ser202/Thr205 and Thr217 correlated with Braak stage for NFTs and with the presence of p-tau Ser202/Thr205 in hippocampus and cortical brain regions. Depending on the phospho-epitope, p-tau in the retina is a potential biomarker for AD and primary tauopathies.

KW - Alzheimer’s disease

KW - Eye

KW - Neurodegeneration

KW - Phosphorylation

KW - Post-mortem

KW - Retina

KW - Tau

KW - Tauopathies

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U2 - 10.1007/s00401-022-02525-1

DO - 10.1007/s00401-022-02525-1

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SN - 0001-6322

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EP - 218

JO - Acta Neuropathologica

JF - Acta Neuropathologica

ER -

Phosphorylated tau in the retina correlates with tau pathology in the brain in Alzheimer’s disease and primary tauopathies

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