Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2

Benefits on cognition from docosahexaenoic acid (DHA,22 : 6 n-3) intake are absent in humans carrying apolipopro-tein Ee4 allele (APOE4), the most important genetic risk factorfor Alzheimer’s disease (AD). To test the hypothesis thatcarryingAPOE4impairs DHA distribution, we evaluatedplasma and brain fatty acid profiles and uptake of [14C]-DHAusingin situcerebral perfusion through the blood–brain barrierin 4- and 13-month-old male and femaleAPOE-targetedreplacement mice (APOE2,APOE3, andAPOE4), fed with aDHA-depleted diet. Cortical and plasma DHA were 9% lowerand 34% higher inAPOE4compared toAPOE2mice,respectively. Brain uptake of [14C]-DHA was 24% lower inAPOE4versusAPOE2mice. A significant relationship wasestablished between DHA and apoE concentrations in thecortex of mice (r2=0.21) and AD patients (r2=0.32).Altogether, our results suggest that lower brain uptake ofDHA inAPOE4than inAPOE2mice may limit the accumu-lation of DHA in cerebral tissues. These data provide amechanistic explanation for the lack of benefit of DHA inAPOE4carriers on cognitive function and the risk of AD.Keywords:Alzheimer’s disease, apolipoprotein E, blood–brain barrier, docosahexaenoic acid, long-chain omega-3polyunsaturated fatty acid

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

Background Following SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic. Methods The study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA. Results The frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD-CD27-) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups. Conclusions The antibody responses to the spike protein, but not the anti-RBD B cell responses diverge between convalescent males and females who develop PCC. Our findings also suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

BackgroundFollowing SARS-CoV-2 infection a significant proportion of convalescent individuals develop the post-COVID condition (PCC) that is characterized by wide spectrum of symptoms encompassing various organs. Even though the underlying pathophysiology of PCC is not known, detection of viral transcripts and antigens in tissues other than lungs raise the possibility that PCC may be a consequence of aberrant immune response to the viral antigens. To test this hypothesis, we evaluated B cell and antibody responses to the SARS-CoV-2 antigens in PCC patients who experienced mild COVID-19 disease during the pre-vaccination period of COVID-19 pandemic.MethodsThe study subjects included unvaccinated male and female subjects who developed PCC or not (No-PCC) after clearing RT-PCR confirmed mild COVID-19 infection. SARS-CoV-2 D614G and omicron RBD specific B cell subsets in peripheral circulation were assessed by flow cytometry. IgG, IgG3 and IgA antibody titers toward RBD, spike and nucleocapsid antigens in the plasma were evaluated by ELISA.ResultsThe frequency of the B cells specific to D614G-RBD were comparable in convalescent groups with and without PCC in both males and females. Notably, in females with PCC, the anti-D614G RBD specific double negative (IgD-CD27-) B cells showed significant correlation with the number of symptoms at acute of infection. Anti-spike antibody responses were also higher at 3 months post-infection in females who developed PCC, but not in the male PCC group. On the other hand, the male PCC group also showed consistently high anti-RBD IgG responses compared to all other groups.ConclusionsThe antibody responses to the spike protein, but not the anti-RBD B cell responses diverge between convalescent males and females who develop PCC. Our findings also suggest that sex-related factors may also be involved in the development of PCC via modulating antibody responses to the SARS-CoV-2 antigens

Kinetics of 13C-DHA before and during fish-oil supplementation in healthy older individuals

Background: Docosahexaenoic acid (DHA) kinetics appear to change with intake, which is an effect that we studied in an older population by using uniformly carbon-13–labeled DHA (13C-DHA). Objective: We evaluated the influence of a fish-oil supplement over 5 mo on the kinetics of 13C-DHA in older persons. Design: Thirty-four healthy, cognitively normal participants (12 men, 22 women) aged between 52 and 90 y were recruited. Two identical kinetic studies were performed, each with the use of a single oral dose of 40 mg 13C-DHA. The first kinetic study was performed before participants started taking a 5-mo supplementation that provided 1.4 g DHA/d plus 1.8 g eicosapentaenoic acid (EPA)/d (baseline); the second study was performed during the final month of supplementation (supplement). In both kinetic studies, blood and breath samples were collected ≤8 h and weekly over 4 wk to analyze 13C enrichment. Results: The time × supplement interaction for 13C-DHA in the plasma was not significant, but there were separate time and supplement effects (P < 0.0001). The area under the curve for plasma 13C-DHA was 60% lower while subjects were taking the supplement than at baseline (P < 0.0001). The uniformly carbon-13–labeled EPA concentration was 2.6 times as high 1 d posttracer while patients were taking the supplement as it was at baseline. The mean (±SEM) plasma 13C-DHA half-life was 4.5 ± 0.4 d at baseline compared with 3.0 ± 0.2 d while taking the supplement (P < 0.0001). Compared with baseline, the mean whole-body half-life was 61% lower while subjects were taking the supplement. The loss of 13C-DHA through β-oxidation to carbon dioxide labeled with carbon-13 increased from 0.085% of dose/h at baseline to 0.208% of dose/h while subjects were taking the supplement. Conclusions: In older persons, a supplement of 3.2 g EPA + DHA/d increased β-oxidation of 13C-DHA and shortened the plasma 13C-DHA half-life. Therefore, when circulating concentrations of EPA and DHA are increased, more DHA is available for β-oxidation. This trial was registered at clinicaltrials.gov as NCT01577004