Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: findings from mouse and human proteomic studies

Aurore Delvenne; Charysse Vandendriessche; Johan Gobom; Marlies Burgelman; Pieter Dujardin; Clint De Nolf; Betty M. Tijms; Charlotte E. Teunissen; Suzanne E. Schindler; Frans Verhey; Inez Ramakers; Pablo Martinez-Lage; Mikel Tainta; Rik Vandenberghe; Jolien Schaeverbeke; Sebastiaan Engelborghs; Ellen De Roeck; Julius Popp; Gwendoline Peyratout; Magda Tsolaki; Yvonne Freund-Levi; Simon Lovestone; Johannes Streffer; Lars Bertram; Kaj Blennow; Henrik Zetterberg; Pieter Jelle Visser; Roosmarijn E. Vandenbroucke; Stephanie J.B. Vos

doi:10.1186/s12987-024-00555-3

Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: findings from mouse and human proteomic studies

Aurore Delvenne^*, Charysse Vandendriessche, Johan Gobom, Marlies Burgelman, Pieter Dujardin, Clint De Nolf, Betty M. Tijms, Charlotte E. Teunissen, Suzanne E. Schindler, Frans Verhey, Inez Ramakers, Pablo Martinez-Lage, Mikel Tainta, Rik Vandenberghe, Jolien Schaeverbeke, Sebastiaan Engelborghs, Ellen De Roeck, Julius Popp, Gwendoline Peyratout, Magda TsolakiYvonne Freund-Levi, Simon Lovestone, Johannes Streffer, Lars Bertram, Kaj Blennow, Henrik Zetterberg, Pieter Jelle Visser, Roosmarijn E. Vandenbroucke, Stephanie J.B. Vos

^*Korrespondierende/r Autor/-in für diese Arbeit

16 Zitate (Scopus)

Abstract

Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. Methods: We used an APP knock-in mouse model, APP^NL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. Results: ChP tissue proteome was dysregulated in APP^NL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. Conclusions: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

Originalsprache	Englisch
Aufsatznummer	58
Zeitschrift	Fluids and Barriers of the CNS
Jahrgang	21
Ausgabenummer	1
ISSN	1743-8454
DOIs	https://doi.org/10.1186/s12987-024-00555-3
Publikationsstatus	Veröffentlicht - 12.2024

Fördermittel

The present study was supported by Alzheimer Nederland and the Research Foundation Flanders (FWO Vlaanderen; 1295223N, 1157621N and 1195019N), and partly supported by the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development) grant numbers 733050502 and 7330505021, an anonymous foundation and EMIF-AD. The EMIF-AD project has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H), Provincial Government of Gipuzkoa (124/16), Kutxa Fundazioa, and by the Carlos III Institute of Health (PI15/00919, PN de I+D+I 2013-2016). The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179). Collection of CSF samples from the Knight ADRC was supported by P30AG06644, P01AG003991, and P01AG026276. HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), and the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C). The authors want to thank the VIB BioImaging Core for training, support and access to the instrument park, and the VIB Proteomics Core for performing the mass spectrometry and for support. The authors also thank Takashi SAITO and Takaomi C. SAIDO for the generation of the APPNL-G-F mouse model. Ms. Delvenne received funding from Alzheimer Nederland (grant number WE.15-2022-01). Dr. Schindler has served on advisory boards for Eisai. The institution of Dr. Vandenberghe has clinical trial agreements (RV as PI) with Alector, Biogen, Denali, EliLilly, J&J, UCB. The institution of Dr. Vandenberghe has consultancy agreements (RV as DSMB member) with AC Immune. Dr. Schaeverbeke is a senior postdoctoral fellow [12Y1623N] of FWO. Dr. Schaeverbeke receives funding from Stichting Alzheimer Onderzoek [SAO-FRA 2021/0022]. Dr. Popp served as a consultant and at advisory boards for the Nestlé Institute of Health Sciences, Ono Pharma, OM Pharma, Schwabe Pharma, Lilly, Roche, and Fujirebio Europe. All his disclosures are unrelated to the present work. The VD cohort was supported by grants from the Swiss National Research Foundation (SNF 320030_204886), Synapsis Foundation—Dementia Research Switzerland (Grant number 2017-PI01). Dr. Blennow has served as a consultant and at advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. Dr. Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Dr. Visser received funding from the European Commission, IMI 2 Joint Undertaking (JU), AMYPAD, grant n° 115952; European Commission, IMI 2 JU, RADAR-AD, grant n°806999; European Commission, IMI 2 JU, EPND, grant n°101034344. The IMI JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Dr. Visser received also funding from Zon-MW, Redefining Alzheimer's disease, grant n°733050824736; and Biogen (Amyloid biomarker study group). Grants were paid to the university. Dr. Vos received funding from ZonMW (SNAP VIMP grant n°7330505021), Stichting Adriana van Rinsum-Ponssen, and the EPND project, which received funding from the European Commision, IMI 2 Joint Undertaking (JU) under grant agreement n°101034344. The IMI JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. All others authors declare that they have no competing interests. The present study was supported by Alzheimer Nederland and the Research Foundation Flanders (FWO Vlaanderen; 1295223N, 1157621N and 1195019N), and partly supported by the Memorabel program of ZonMw (the Netherlands Organization for Health Research and Development) grant numbers 733050502 and 7330505021, an anonymous foundation and EMIF-AD. The EMIF-AD project has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H), Provincial Government of Gipuzkoa (124/16), Kutxa Fundazioa, and by the Carlos III Institute of Health (PI15/00919, PN de I+D+I 2013-2016). The Lausanne study was funded by a grant from the Swiss National Research Foundation (SNF 320030_141179). Collection of CSF samples from the Knight ADRC was supported by P30AG06644, P01AG003991, and P01AG026276. HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356; #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), and the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C). The authors want to thank the VIB BioImaging Core for training, support and access to the instrument park, and the VIB Proteomics Core for performing the mass spectrometry and for support. The authors also thank Takashi SAITO and Takaomi C. SAIDO for the generation of the APP mouse model. The present study was supported by Alzheimer Nederland grant number WE.15-2022-01, the Research Foundation Flanders (FWO Vlaanderen; 1295223N, 1157621N and 1195019N), and partly supported by ZonMw (the Netherlands Organization for Health Research and Development) grant numbers 733050502 and 7330505021, an anonymous foundation and EMIF-AD. The EMIF-AD project has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA companies’ in kind contribution.

Träger	Trägernummer
Alzheimer Nederland and the Research Foundation Flanders
EMIF
Alzheimer's Association
Stichting Adriana van Rinsum-Ponssen
Secretaría de Estado de Investigacion, Desarrollo e Innovacion
European Federation of Pharmaceutical Industries and Associations
Biogen
Department of Health of the Basque Government
Horizon 2020 Framework Programme
Obra Social Kutxa-Fundazioa
Memorabel program of ZonMw
Innovative Medicines Initiative
AD Strategic Fund
European Union's Seventh Framework Program	FP7/2007-2013
Vetenskapsrådet	2022-01018, 2019-02397, 2023-00356
Provincial Government of Gipuzkoa	124/16
European Commission	115372, 101053962
European Commission within the 5th framework program	37670, QLRT-2001-2455
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	P30AG06644, P01AG003991, 320030_141179, P01AG026276, 320030_204886
AMYPAD	IMI 2 JU, 806999, 115952
EPND	101034344
Fonds Wetenschappelijk Onderzoek	1195019N, 1157621N, 1295223N
Stichting Alzheimer Onderzoek	SAO-FRA 2021/0022
Seventh Framework Programme	FP7/2007-2013
Stiftung Synapsis - Alzheimer Forschung Schweiz AFS	2017-PI01
Redefining Alzheimer's disease	733050824736
Instituto de Salud Carlos III	PI15/00919
European Union’s Horizon Europe research and innovation programme	-71320, 101053962
ZonMw	733050502
Alzheimer Nederland	WE.15-2022-01
SNAP VIMP	7330505021

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SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik

DFG-Fachsystematik

2.23-06 Molekulare und zelluläre Neurologie und Neuropathologie

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10.1186/s12987-024-00555-3

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Delvenne, A., Vandendriessche, C., Gobom, J., Burgelman, M., Dujardin, P., De Nolf, C., Tijms, B. M., Teunissen, C. E., Schindler, S. E., Verhey, F., Ramakers, I., Martinez-Lage, P., Tainta, M., Vandenberghe, R., Schaeverbeke, J., Engelborghs, S., De Roeck, E., Popp, J., Peyratout, G., ... Vos, S. J. B. (2024). Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: findings from mouse and human proteomic studies. Fluids and Barriers of the CNS, 21(1), Artikel 58. https://doi.org/10.1186/s12987-024-00555-3

@article{e403ab44824e4fb8b9b3a3e579e2d1ee,

title = "Involvement of the choroid plexus in Alzheimer{\textquoteright}s disease pathophysiology: findings from mouse and human proteomic studies",

abstract = "Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer{\textquoteright}s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. Methods: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. Results: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. Conclusions: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.",

author = "Aurore Delvenne and Charysse Vandendriessche and Johan Gobom and Marlies Burgelman and Pieter Dujardin and \{De Nolf\}, Clint and Tijms, \{Betty M.\} and Teunissen, \{Charlotte E.\} and Schindler, \{Suzanne E.\} and Frans Verhey and Inez Ramakers and Pablo Martinez-Lage and Mikel Tainta and Rik Vandenberghe and Jolien Schaeverbeke and Sebastiaan Engelborghs and \{De Roeck\}, Ellen and Julius Popp and Gwendoline Peyratout and Magda Tsolaki and Yvonne Freund-Levi and Simon Lovestone and Johannes Streffer and Lars Bertram and Kaj Blennow and Henrik Zetterberg and Visser, \{Pieter Jelle\} and Vandenbroucke, \{Roosmarijn E.\} and Vos, \{Stephanie J.B.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1186/s12987-024-00555-3",

language = "English",

volume = "21",

journal = "Fluids and Barriers of the CNS",

issn = "1743-8454",

publisher = "BioMed Central Ltd",

number = "1",

}

Delvenne, A, Vandendriessche, C, Gobom, J, Burgelman, M, Dujardin, P, De Nolf, C, Tijms, BM, Teunissen, CE, Schindler, SE, Verhey, F, Ramakers, I, Martinez-Lage, P, Tainta, M, Vandenberghe, R, Schaeverbeke, J, Engelborghs, S, De Roeck, E, Popp, J, Peyratout, G, Tsolaki, M, Freund-Levi, Y, Lovestone, S, Streffer, J, Bertram, L, Blennow, K, Zetterberg, H, Visser, PJ, Vandenbroucke, RE & Vos, SJB 2024, 'Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: findings from mouse and human proteomic studies', Fluids and Barriers of the CNS, Jg. 21, Nr. 1, 58. https://doi.org/10.1186/s12987-024-00555-3

TY - JOUR

T1 - Involvement of the choroid plexus in Alzheimer’s disease pathophysiology

T2 - findings from mouse and human proteomic studies

AU - Delvenne, Aurore

AU - Vandendriessche, Charysse

AU - Gobom, Johan

AU - Burgelman, Marlies

AU - Dujardin, Pieter

AU - De Nolf, Clint

AU - Tijms, Betty M.

AU - Teunissen, Charlotte E.

AU - Schindler, Suzanne E.

AU - Verhey, Frans

AU - Ramakers, Inez

AU - Martinez-Lage, Pablo

AU - Tainta, Mikel

AU - Vandenberghe, Rik

AU - Schaeverbeke, Jolien

AU - Engelborghs, Sebastiaan

AU - De Roeck, Ellen

AU - Popp, Julius

AU - Peyratout, Gwendoline

AU - Tsolaki, Magda

AU - Freund-Levi, Yvonne

AU - Lovestone, Simon

AU - Streffer, Johannes

AU - Bertram, Lars

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Visser, Pieter Jelle

AU - Vandenbroucke, Roosmarijn E.

AU - Vos, Stephanie J.B.

PY - 2024/12

Y1 - 2024/12

N2 - Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. Methods: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. Results: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. Conclusions: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

AB - Background: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. Methods: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. Results: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. Conclusions: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

UR - https://www.scopus.com/pages/publications/85198839953

U2 - 10.1186/s12987-024-00555-3

DO - 10.1186/s12987-024-00555-3

M3 - Journal articles

C2 - 39020361

AN - SCOPUS:85198839953

SN - 1743-8454

VL - 21

JO - Fluids and Barriers of the CNS

JF - Fluids and Barriers of the CNS

IS - 1

M1 - 58

ER -

Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: findings from mouse and human proteomic studies

Abstract

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