Home > Articles > Published articles > Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer's disease patients |
Date: | 2022 |
Abstract: | Objective: The purpose of this study was to examine the levels of cerebrospinal fluid (CSF) apolipoprotein E (apoE) species in Alzheimer's disease (AD) patients. Methods: We analyzed two CSF cohorts of AD and control individuals expressing different APOE genotypes. Moreover, CSF samples from the TgF344-AD rat model were included. Samples were run in native- and SDS-PAGE under reducing or non-reducing conditions (with or without β-mercaptoethanol). Immunoprecipitation combined with mass spectrometry or western blotting analyses served to assess the identity of apoE complexes. Results: In TgF344-AD rats expressing a unique apoE variant resembling human apoE4, a ~35-kDa apoE monomer was identified, increasing at 16. 5 months compared with wild-types. In humans, apoE isoforms form disulfide-linked dimers in CSF, except apoE4, which lacks a cysteine residue. Thus, controls showed a decrease in the apoE dimer/monomer quotient in the APOE ε3/ε4 group compared with ε3/ε3 by native electrophoresis. A major contribution of dimers was found in APOE ε3/ε4 AD cases, and, unexpectedly, dimers were also found in ε4/ε4 AD cases. Under reducing conditions, two apoE monomeric glycoforms at 36 kDa and at 34 kDa were found in all human samples. In AD patients, the amount of the 34-kDa species increased, while the 36-kDa/34-kDa quotient was lower compared with controls. Interestingly, under reducing conditions, a ~100-kDa apoE complex, the identity of which was confirmed by mass spectrometry, also appeared in human AD individuals across all APOE genotypes, suggesting the occurrence of aberrantly resistant apoE aggregates. A second independent cohort of CSF samples validated these results. Conclusion: These results indicate that despite the increase in total apoE content the apoE protein is altered in AD CSF, suggesting that function may be compromised. |
Grants: | Instituto de Salud Carlos III PI15/00665 Instituto de Salud Carlos III PI19-01359 Instituto de Salud Carlos III PI14/01126 Instituto de Salud Carlos III PI17/01019 Instituto de Salud Carlos III PI20/01473 Instituto de Salud Carlos III INT16/00171 Instituto de Salud Carlos III PI18/00435 Instituto de Salud Carlos III PI14/1561 Instituto de Salud Carlos III PI17/01896 Instituto de Salud Carlos III PI20/1330 Instituto de Salud Carlos III PI18/00893 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT002/16/00408 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT006/17/00119 Agència de Gestió d'Ajuts Universitaris i de Recerca SLT006/17/00125 Ministerio de Economía y Competitividad SEV-2017-0723 Ministerio de Ciencia, Innovación y Universidades PID2019-107738RB-I00 European Research Council #681712 European Commission. Horizon 2020 860197 European Commission JPND2021-00694 European Commission JPND2019-466-236 |
Note: | Altres ajuts: Swedish Research Council (#2018-02532); Swedish State Support for Clinical Research (#ALFGBG-720931); Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862); AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C); Olav Thon Foundation; Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor; Hjärnfonden, Sweden (#FO2019-0228); UK Dementia Research Institute (UKDRI-1003); Swedish Research Council (#2017-00915); Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615); Swedish Alzheimer Foundation (#AF-742881); Hjärnfonden, Sweden (#FO2017-0243); Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986); National Institute of Health (NIH), USA (grant #1R01AG068398-01); Alzheimer's Association 2021 Zenith Award (ZEN-21-848495); CIBERNED program (Program 1, Alzheimer Disease to AL and SIGNAL study, www.signalstudy.es); National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, R01AG061566); Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut; Fondo Europeo de Desarrollo Regional (FEDER "Investing in your future"); Direcció General de Ciència I Investigació, Generalitat Valenciana (AICO/2021/308). |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Alzheimer's disease ; Apoe ; Biomarker ; Aberrant complexes ; Cerebrospinal fuid ; Glycoform imbalance |
Published in: | Alzheimer's research & therapy, Vol. 14 Núm. 1 (december 2022) , p. 161, ISSN 1758-9193 |
19 p, 3.1 MB |