TY - JOUR

T1 - Endo-lysosomal protein concentrations in CSF from patients with frontotemporal dementia caused by CHMP2B mutation

AU - Toft, Anders

AU - Sjödin, Simon

AU - Simonsen, Anja Hviid

AU - Ejlerskov, Patrick

AU - Roos, Peter

AU - Musaeus, Christian Sandøe

AU - Henriksen, Emil Elbæk

AU - Nielsen, Troels Tolstrup

AU - Brinkmalm, Ann

AU - Blennow, Kaj

AU - Zetterberg, Henrik

AU - Nielsen, Jørgen Erik

N1 - Funding Information: K.B. is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721, and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer's Association 2021 Zenith Award (ZEN-21-848495). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003), Aase & Ejnar Danielsens Fond (19-10-0192), P.A. Messerschmidt & Hustrus Fond, Lægeforeningens Forskningsfond. Funding Information: K.B. is supported by the Swedish Research Council (#2017‐00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB‐201809‐2016615), the Swedish Alzheimer Foundation (#AF‐930351, #AF‐939721, and #AF‐968270), Hjärnfonden, Sweden (#FO2017‐0243 and #ALZ2022‐0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF‐agreement (#ALFGBG‐715986 and #ALFGBG‐965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019‐466‐236), the National Institute of Health (NIH), USA, (grant #1R01AG068398‐01), and the Alzheimer's Association 2021 Zenith Award (ZEN‐21‐848495). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018‐02532), the European Research Council (#681712 and #101053962), Swedish State Support for Clinical Research (#ALFGBG‐71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809‐2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF‐21‐831376‐C, #ADSF‐21‐831381‐C, and #ADSF‐21‐831377‐C), the Bluefield Project, the Olav Thon Foundation, the Erling‐Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022‐0270), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021‐00694), and the UK Dementia Research Institute at UCL (UKDRI‐1003), Aase & Ejnar Danielsens Fond (19‐10‐0192), P.A. Messerschmidt & Hustrus Fond, Lægeforeningens Forskningsfond. Publisher Copyright: © 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

PY - 2023

Y1 - 2023

N2 - Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD). 31 members of the Danish CHMP2B-FTD family were included. We used solid-phase extraction and parallel reaction monitoring mass spectrometry. Six protein levels were significantly altered in CHMP2B-FTD compared with controls. Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.

AB - Introduction: Increasing evidence implicates proteostatic dysfunction as an early event in the development of frontotemporal dementia (FTD). This study aimed to explore potential cerebrospinal fluid (CSF) biomarkers associated with the proteolytic systems in genetic FTD caused by CHMP2B mutation. Methods: Combining solid-phase extraction and parallel reaction monitoring mass spectrometry, a panel of 47 peptides derived from 20 proteins was analyzed in CSF from 31 members of the Danish CHMP2B-FTD family. Results: Compared with family controls, mutation carriers had significantly higher levels of complement C9, lysozyme and transcobalamin II, and lower levels of ubiquitin, cathepsin B, and amyloid precursor protein. Discussion: Lower CSF ubiquitin concentrations in CHMP2B mutation carriers indicate that ubiquitin levels relate to the specific disease pathology, rather than all-cause neurodegeneration. Increased lysozyme and complement proteins may indicate innate immune activation. Altered levels of amyloid precursor protein and cathepsins have previously been associated with impaired lysosomal proteolysis in FTD. Highlights: CSF markers of proteostasis were explored in CHMP2B-mediated frontotemporal dementia (FTD). 31 members of the Danish CHMP2B-FTD family were included. We used solid-phase extraction and parallel reaction monitoring mass spectrometry. Six protein levels were significantly altered in CHMP2B-FTD compared with controls. Lower CSF ubiquitin levels in patients suggest association with disease mechanisms.

KW - amyloid precursor protein

KW - biomarkers

KW - cathepsin B

KW - cerebrospinal fluid

KW - complement C9

KW - frontotemporal dementia

KW - lysozyme

KW - proteomics

KW - transcobalamin II

KW - ubiquitin

U2 - 10.1002/dad2.12402

DO - 10.1002/dad2.12402

M3 - Journal article

C2 - 36815874

AN - SCOPUS:85152370046

VL - 15

JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring

SN - 2352-8729

IS - 1

M1 - e12402

ER -