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| Home > Articles > Published articles > Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer's disease patients |
(Universitat de Barcelona. Institut de Neurociències) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Institut d'Investigació Biomèdica Sant Pau) (Universitat de Barcelona. Institut de Neurociències) (Hong Kong Center for Neurodegenerative Diseases) (Clinical Neurochemistry Laboratory. Sahlgrenska University Hospital)| 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 |
