| 1. |
- Almeida, Francisco C., et al.
(författare)
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APOE genotype dictates lipidomic signatures in primary human hepatocytes
- 2024
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 65:2
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein E (APOE) genetic variants are most notably known for their divergent impact on the risk of developing Alzheimer's disease. While APOE genotype has been consistently shown to modulate lipid metabolism in a variety of cellular contexts, the effect of APOE alleles on the lipidome in hepatocytes is unknown. In this study, we investigated the contribution of APOE alleles to lipidomic profiles of donor -derived primary human hepatocytes from 77 subjects. Lipidomic data obtained by liquid chromatography -mass spectrometry were analyzed across e2/e3, e3/e3, and e3/e4 genotypes to reveal how APOE modulates lipid relative levels over age and between groups. Hepatic APOE concentration, measured by ELISA, was assessed for correlation with lipid abundance in subjects grouped as per APOE genotype and sex. APOE genotype -specific differential lipidomic signatures associated with age for multiple lipid classes but did not differ between sexes. Compared to e2/e3, e3/e4 hepatocytes had higher abundance of acylcarnitines (AC) and acylphosphatidylglycerol (AcylPG) as a class, as well as higher medium and long -chain ACs, AcylPG, phosphatidylglycerol (PG), bis(monoacylglycerol)phosphate (BMP), monoacylglycerol (MG) and diacylglycerol (DG) species. The e3/e4 hepatocytes also exhibited a higher abundance of medium and long -chain ACs compared to the e3/e3 hepatocytes. Only in the e3/e4 hepatocytes, APOE concentration was lower and showed a negative correlation with BMP levels, specifically in females. APOE genotype dictates a differential lipidome in primary human hepatocytes. The lipids involved suggest mitochondrial dysfunction with accompanying alterations in neutral lipid storage, reflective of a general disturbance of free fatty acid metabolism in human hepatocytes with the e4 allele.
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| 2. |
- Giannisis, Andreas, 1993-
(författare)
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Peripheral apolipoprotein E and its emerging role in neurodegenerative disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human apolipoprotein E gene (APOE) is polymorphic and coding for three common alleles; ε2, ε3, and ε4. Carriers of the ε4 allele are at a higher risk of developing sporadic late-onset Alzheimer’s Disease (AD). This association appears to be influenced by inherited traits, race, and sex. The connection between APOE genotype and AD-related pathological processes has been studied excessively, however, less attention has been devoted to the apolipoprotein E (apoE) protein levels per se, most possibly due to the inconsistent results presented in studies assessing potential links between cerebrospinal fluid (CSF) apoE levels and AD, and because systemic apoE cannot cross the blood-brain barrier (BBB). Nevertheless, low plasma apoE levels were found to enhance AD and dementia risk, with the APOE ε4 genotype influencing this risk by promoting a reduction of the plasma apoE levels in some populations. In this thesis, we speculate that peripheral apoE-dependent mechanisms are linked to neurodegeneration. To address this hypothesis, we performed a set of clinical and experimental studies. In the first three studies, we aimed to determine whether hepatic APOE ε4 genotype, plasma apoE levels, and diet are linked to brain function and cognition by utilizing a mouse model with humanized-livers that are characterized by the presence of human apoE only in the plasma. A comparison between the brains of APOE ε4/ε4 and APOE ε2/ε3 humanized-liver mice revealed altered endogenous murine apoe levels as well as altered levels of synaptic, neuroinflammatory, and insulin signaling-related markers in the cortex and hippocampus. Higher plasma apoE4 levels were also linked to these associations, mainly in the hippocampus of the humanized APOE ε4/ε4 liver mice. A similar, though less pronounced, effect was observed in the brains of APOE ε3/ε3 humanized-liver mice that were fed a high-fat, versus a normal diet. Utilizing the plasma from APOE ε3/ε3 humanized-liver mice, we further observed that the distribution of apoE3 in plasma lipoparticles differed between sexes. In addition, higher total plasma apoE3 levels were beneficial to the activity levels but appeared to have a negative impact on cognition in these mice. In the remaining studies, we aimed to determine how plasma apoE levels, apoE isoform distribution, and the formation of monomers and disulfide-linked homodimers and heterodimers with apolipoprotein A-II (apoA-II) are influenced by APOE genotype and AD. For that purpose, we studied two cohorts of Norwegian, Black/African-American (B/AA), and non-Hispanic white (NHW) cognitively healthy subjects and patients with AD or mild cognitive impairment (MCI). Only in Norwegian individuals, we observed lower levels of plasma apoE due to AD and APOE ε4 genotype. In addition, in these subjects, the apoE monomer/dimer profile seemed to be influenced by AD status. In the cohort of B/AAs and NHWs, these associations were absent. In both cohorts, we observed associations between plasma apoE levels and CSF AD biomarker levels. Lastly, B/AA subjects presented the highest plasma apoE levels with APOE ε4/ε4-carrying subjects exhibiting significantly higher plasma apoE levels than NHW APOE ε4/ε4 subjects.Overall, our studies suggest that hepatic APOE genotype and plasma apoE levels are associated with AD-related neuropathological changes which seem to be influenced by other factors like race and diet. Whether this influence is due to differences in apoE levels or apoE function (i.e. different distribution between lipoparticles) remains to be investigated in future studies.
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| 3. |
- Giannisis, Andreas, 1993-, et al.
(författare)
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Plasma apolipoprotein E levels, isoform composition, and dimer profile in relation to plasma lipids in racially diverse patients with Alzheimer’s disease and mild cognitive impairment
- 2023
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Ingår i: Alzheimer's Research & Therapy. - : Springer Nature. - 1758-9193. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background The APOEε4-promoted risk of Alzheimer’s disease (AD) is lower in Black/African-Americans (B/AAs), compared to non-Hispanic whites (NHWs). Previous studies reported lower plasma apolipoprotein E (apoE) levels in NHW APOEε4-carriers compared to non-carriers, and low plasma apoE levels were directly associated with an increased risk of AD and all dementia. We further showed that APOEε3/ε3 AD patients exhibited reduced plasma apoE dimers compared to corresponding control subjects. Whether plasma apoE levels and apoE dimer formation differ between races/ethnicities and therefore may help explain AD risk racial disparity remains to be elucidated.Methods Using mass spectrometry, we determined total plasma apoE and apoE isoform levels in a cohort of B/AAs (n = 58) and NHWs (n = 67) including subjects with normal cognition (B/AA: n = 25, NHW: n = 28), mild cognitive impairment (MCI) (B/AA: n = 24, NHW: n = 24), or AD dementia (B/AA: n = 9, NHW: n = 15). Additionally, we used non-reducing western blot analysis to assess the distribution of plasma apoE into monomers/disulfide-linked dimers. Plasma total apoE, apoE isoform levels, and % apoE monomers/dimers were assessed for correlations with cognition, cerebrospinal fluid (CSF) AD biomarkers, sTREM2, neurofilament light protein (NfL), and plasma lipids.Results Plasma apoE was predominantly monomeric in both racial groups and the monomer/dimer distribution was not affected by disease status, or correlated with CSF AD biomarkers, but associated with plasma lipids. Plasma total apoE levels were not related to disease status and only in the NHW subjects we observed lower plasma apoE levels in the APOEε4/ε4-carriers. Total plasma apoE levels were 13% higher in B/AA compared to NHW APOEε4/ε4 subjects and associated with plasma high-density lipoprotein (HDL) in NHW subjects but with low-density lipoprotein levels (LDL) in the B/AA subjects. Higher plasma apoE4 levels, exclusively in APOEε3/ε4 B/AA subjects, were linked to higher plasma total cholesterol and LDL levels. In the controls, NHWs and B/AAs exhibited opposite associations between plasma apoE and CSF t-tau.Conclusions The previously reported lower APOEε4-promoted risk of AD in B/AA subjects may be associated with differences in plasma apoE levels and lipoprotein association. Whether differences in plasma apoE levels between races/ethnicities result from altered APOEε4 expression or turnover, needs further elucidation.
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