Effect of APOE epsilon4 allele on levels of apolipoproteins E, J, and D, and redox signature in circulating extracellular vesicles from cognitively impaired with no dementia participants converted to Alzheimer's disease

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Posted: 2021-09-20 19:00:00
Alzheimers Dement (Amst) . 2021 Sep 14;13(1):e12231. doi: 10.1002/dad2.12231. eCollection 2021. Affiliations Expand Affiliations 1 INRS-Centre Armand-Frappier Santé-Biotechnologie Laval Quebec Canada. 2 Institute of Nutrition and Functional Foods Québec Québec Canada. 3 Centre d'excellence sur le vieillissement de Québec CHU de Québec-Université Laval Research Centre VITAM-Centre de recherche en santé durable Québec Québec Canada. 4 Faculty of Pharmacy Laval University Québec Québec Canada. Item in Clipboard Mohamed Raâfet Ben Khedher et al. Alzheimers Dement (Amst). 2021. Show details Display options Display options Format Alzheimers Dement (Amst) . 2021 Sep 14;13(1):e12231. doi: 10.1002/dad2.12231. eCollection 2021. Affiliations 1 INRS-Centre Armand-Frappier Santé-Biotechnologie Laval Quebec Canada. 2 Institute of Nutrition and Functional Foods Québec Québec Canada. 3 Centre d'excellence sur le vieillissement de Québec CHU de Québec-Université Laval Research Centre VITAM-Centre de recherche en santé durable Québec Québec Canada. 4 Faculty of Pharmacy Laval University Québec Québec Canada. Item in Clipboard CiteDisplay options Display options Format Abstract Introduction: The substantial link between apolipoprotein E (APOE) ε4 allele and oxidative stress may underlie enhanced Alzheimer's disease (AD) risk. Here, we studied the impact of APOE ε4 on the level of apolipoproteins with antioxidant activities along with oxidative markers in circulating extracellular vesicles (cEVs) and plasma from cognitively impaired-not demented (CIND) individuals converted to AD (CIND-AD). Methods: Apolipoproteins E, J, and D and antioxidant response markers were determined in cEVs and plasma using immunoblotting, electrochemical examination, and spectrofluorimetry. Results: Total antioxidant capacity and apolipoprotein D levels in cEVs, as judged by regression analysis and cognitive performance correlations, allowed us to differentiate CIND APOE ε4 carriers from controls and to predict their progression to AD 5 years later. Discussion: Our findings support the pathological redox linkage between APOE ε4 and AD onset and suggest the use of cEVs oxidative signature in early AD diagnosis. Keywords: Alzheimer's disease; apolipoprotein E; extracellular vesicles; oxidative stress. © 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association. Conflict of interest statement The authors report that they have no conflicts of interest to disclose. Figures FIGURE 1 Visualization and characterization of circulating… FIGURE 1 Visualization and characterization of circulating extracellular vesicles (cEVs) isolated from plasma. A, cEV… FIGURE 1 Visualization and characterization of circulating extracellular vesicles (cEVs) isolated from plasma. A, cEV images as acquired by transmission electron microscopy, bar represents 100 nm. B, Size distribution and concentration of cEVs examined by NTA using the NanoSight‐NS300. C, Immunoblot detection of EV protein markers and non‐associated proteins. D, Total cEV protein profile revealed by Coomassie blue staining FIGURE 2 Plasma and circulating extracellular vesicle… FIGURE 2 Plasma and circulating extracellular vesicle (cEV) levels of oxidative factors. A, Plasma TAC,… FIGURE 2 Plasma and circulating extracellular vesicle (cEV) levels of oxidative factors. A, Plasma TAC, (B) cEVs protein carbonyls, (C) cEVs apolipoprotein D, (D) plasma apolipoprotein D, (E) cEVs apolipoprotein J/D ratio (N = 36, including 21 controls and 15 CIND‐AD). Each point represents the ratio of marker band intensity and the corresponding total protein intensity stained with the Coomassie blue. Statistical analysis was performed using the nonparametric Mann‐Whitney test for (A), (C), (D), and (E) parameters and parametric student t test for (B) with a, P < .05 and aa, P < .01 versus controls FIGURE 3 Linear regression analysis between the… FIGURE 3 Linear regression analysis between the cognitive performances and the studied markers: (A) plasma… FIGURE 3 Linear regression analysis between the cognitive performances and the studied markers: (A) plasma total antioxidant capacity, (B) circulating extracellular vesicle (cEV) protein carbonyls, (C) cEV apolipoprotein D, (D) plasma apolipoprotein D, (E) cEV apolipoprotein J/D ratio (N = 36, including 21 controls and 15 cognitively impaired, no dementia‐Alzheimer's disease). Abbreviations: MMSE, Mini‐Mental State Examination; r, correlation coefficient; p, significance. Statistical analysis was performed using the correlation coefficient (Pearson r) and P‐values were determined using Pearson correlation FIGURE 4 Plasma and circulating extracellular vesicle… FIGURE 4 Plasma and circulating extracellular vesicle (cEV) levels of oxidative factors according to APOE… FIGURE 4 Plasma and circulating extracellular vesicle (cEV) levels of oxidative factors according to APOE isoform: (A) plasma total antioxidant capacity, (B) cEV protein carbonyls, (C) cEV apolipoprotein D, (D) plasma apolipoprotein D, (E) cEV apolipoprotein J/D ratio (N = 36, including 21 controls, 10 CIND‐AD APOE ε4+, and 5 CIND‐AD APOE ε4−). Abbreviations: CIND, cognitively impaired, no dementia; AD, Alzheimer's disease; APOE, apolipoprotein E; (+), ε4 carriers; (−), ε4 non‐carriers. Each point represents the ratio of marker band intensity and the corresponding total protein intensity stained with the Coomassie blue. Statistical analysis was performed using the nonparametric Kruskal‐Wallis test followed by Dunn test for (A), (C), (D), and (E) parameters and the one‐way analysis of variance (ANOVA) followed by the Dunnett post hoc test for (B). a, P < .05 and aa, P < .01 versus controls FIGURE 5 Receiver operating characteristic (ROC) curve… FIGURE 5 Receiver operating characteristic (ROC) curve analysis according to apolipoprotein E ( APOE )… FIGURE 5 Receiver operating characteristic (ROC) curve analysis according to apolipoprotein E (APOE) isoform. The plot represents the performance of plasma and circulating extracellular vesicle (cEV) oxidative factors to discriminate controls from total CIND‐AD, CIND‐AD APOE ε4+, and CIND‐AD APOE ε4− participants: (A, B, C) plasma total antioxidant capacity, (D, E, F) cEV apolipoprotein D, (G, H, I) cEV apolipoprotein J/D ratio, (J, K, L) cEV protein carbonyls level. AUC, area under the curve; Std, standard; 95% CI, 95% confidence intervals; ns, not significant References 2020 Alzheimer's disease facts and figures. Alzheimers Dement. 2020;16(3):391‐460. 10.1002/alz.12068 - DOI Weller J, Budson A. Current understanding of Alzheimer's disease diagnosis and treatment. F1000Res. 2018;7. F1000 Faculty Rev‐1161. Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S, Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993;342(8873):697‐699. - PubMed Belloy ME, Napolioni V, Greicius MD. A quarter century of APOE and Alzheimer's disease: progress to date and the path forward. Neuron. 2019;101(5):820‐838. - PMC - PubMed Turney IC, Chesebro AG, Rentería MA, et al. APOE ε4 and resting‐state functional connectivity in racially/ethnically diverse older adults. Alzheimers Dement. 2020;12(1):e12094‐e12094. - PMC - PubMed Show all 50 references LinkOut - more resources Miscellaneous [x] Cite Copy Format: Send To [x]

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