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Title: Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer's disease patients.
Author: Lennol, Matthew Paul
Sánchez-Domínguez, Irene
Cuchillo-Ibañez, Inmaculada
Camporesi, Elena
Brinkmalm, Gunnar
Alcolea, Daniel
Fortea, Juan
Lleó Bisa, Alberto
Soria, Guadalupe
Aguado Tomàs, Fernando
Zetterberg, Henrik
Blennow, Kaj
Sáez-Valero, Javier
Keywords: Malaltia d'Alzheimer
Líquid cefalorraquidi
Alzheimer's disease
Cerebrospinal fluid
Issue Date: 2-Nov-2022
Publisher: BioMed Central
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.
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It is part of: Alzheimers Research & Therapy, 2022, vol. 14, num. 161, p. 1-19
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ISSN: 1758-9193
Appears in Collections:Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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