| 1. |
- Almeida, Francisco C., et al.
(author)
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APOE genotype dictates lipidomic signatures in primary human hepatocytes
- 2024
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In: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 65:2
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Journal article (peer-reviewed)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. |
- Baker, Crystal, et al.
(author)
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Effects of Alzheimer's peptide and alpha 1-antichymotrypsin on astrocyte gene expression
- 2007
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In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 28:1, s. 51-61
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Journal article (peer-reviewed)abstract
- We employed gene array technology to investigate the effects of alpha 1-antichymotrypsin (ACT), soluble or fibrillar Alzheimer's peptide (A beta(1-42)) alone and the combination of ACT/A beta(1-42) on human astrocytes. Using a 1.2-fold change as significance threshold, 398 astrocyte genes showed altered expression in response to these treatments compared to controls. Of the 276 genes affected by the ACT/soluble A beta(1-42) combination, 195 (70.6%) were suppressed. The ACT/fibrillar A beta(1-42) combination affected expression of 64 genes of which 58 (90.5%) were up-regulated. The most prominent gene expression changes in response to the ACT/soluble A beta(1-42), were the down-regulation of at least 60 genes involved in transcription, signal transduction, apoptosis and neurogenesis. The ACT/fibril A beta(1-42) increased the expression of genes involved in transcription regulation and signal transduction. Surprisingly, gene expression of astrocytes exposed to soluble or fibrillar A beta(1-42) alone was largely unaffected. Thus, the molecular forms generated by the combination of ACT/A beta(1-42) alter expression of astrocyte genes more profoundly in breadth and magnitude than soluble or fibrillar A beta(1-42) alone, suggesting that pathogenic effects of A beta(1-42) may occur as a consequence of its association with other proteins. (c) 2005 Elsevier Inc. All rights reserved.
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| 3. |
- Edlund, Anna, 1983-, et al.
(author)
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Elucidating the effects of a high fat diet on markers of brain insulin signaling, gliosis and synaptic integrity in mice with humanized APOEε3
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Other publication (other academic/artistic)abstract
- Background: Mid-life obesity is associated with an increased risk of dementia, including Alzheimer’s disease (AD). Elevated circulating free fatty acids were previously shown tohamper insulin transport across the blood-brain barrier (BBB) and dysfunctional brain insulin signaling in turn negatively affects cognition by modulating excitatory synapses. Addressing links between diet, lipid metabolism and cognition in vivo is complicated by species-specific differences in lipid metabolism. Here we used FRGN mice with humanized livers of the AD risk-neutral APOEε3/ε3 genotype to explore the effects of a high-fat diet (HFD) on markers of insulin signaling, gliosis and synaptic integrity in the brain.Methods: FRGN mice (n=11) with humanized livers of the APOEε3/ε3 genotype were fed normal chow (n=3) versus a HFD for 12 (n=5) or 20 weeks (n=3). Brain cortical and hippocampal tissues were biochemically analysed for changes in markers of gliosis, synaptic integrity, glucose transporters and insulin signaling. Immunohistochemistry (IHC) was used to assess whether the identified changes replicated at the histological level.Results: Humanization of the mouse liver produced human-like levels of plasma apolipoprotein B and low-density lipoprotein, which were further increased by a 12 week HFD. Mice on the HFD exhibited increased phosphorylation of the insulin receptor substrate 1 (IRS-1) at Ser-616, previously linked to brain insulin resistance, in parallel with reduced cortical marker levels of synaptic AMPAR. Markers of hippocampal insulin signaling were unaffected by the HFD however we observed an increase in the astrocytic marker GFAP but not the microglia- associated IBA1, and intracellular apolipoprotein E (apoE) levels alongside altered levels of the postsynaptic AMPA receptors and PSD-95. Hippocampal and cortical marker levels of the pre-synaptic synaptophysin were increased. The observed changes in the brain tissues were subtle and only alterations in the synaptophysin levels were corroborated using IHC.Conclusions: Our findings suggest that a HFD alters insulin signaling specifically in the cortex, and the levels of AMPAR, PSD-95, synaptophysin and apoE in the brains of FRGN mice with humanized livers, in the absence of microglia activation. These findings support a key role of the diet in brain health with implications for diseases like AD.
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| 4. |
- Edlund, Anna K., et al.
(author)
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Impact of high-fat diet on brain integrity in APOEε3 humanized liver mice
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Other publication (other academic/artistic)abstract
- Mid-life obesity and dysfunctional brain insulin signaling are associated with an increased risk of dementia. We used FRGN mice (n=11) with humanized APOEε3/ε3 livers to explore the effects of a high-fat-diet (HFD) on markers of insulin signaling, gliosis and synaptic integrityin brain cortical and hippocampal tissues using western blotting and immunohistochemistry.Humanization of the mouse liver produced human-like levels of plasma apolipoprotein B and low-density lipoprotein, which were increased by a 12 week HFD. Mice on the HFD exhibitedincreased phosphorylation of insulin receptor substrate 1 (IRS-1-Ser612) and reduced cortical levels of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Hippocampal insulin signaling markers were unaffected but the astrocytic marker glial fibrillary acidic protein (GFAP), apolipoprotein E (apoE) and synatophysin were elevated alongsidealtered levels of AMPAR. Our results acquired in a humanized liver mouse model support a key role of the diet in brain health, with implications for diseases like AD.
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| 5. |
- Edlund, Anna K., 1983-, et al.
(author)
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Plasma Apolipoprotein E3 and Glucose Levels Are Associated in APOE ɛ3/ɛ4 Carriers
- 2021
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 81:1, s. 339-354
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Journal article (peer-reviewed)abstract
- Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain.Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, and neuropsychological test scores.Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI.Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores.Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD.
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| 6. |
- Edlund, Anna, 1983-
(author)
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Links between plasma apoE and glucose metabolism, brain insulin signaling, and synaptic integrity : Relevance to Alzheimer’s disease pathophysiology
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Human apolipoprotein E (apoE) exists as three main isoforms called apoE2, apoE3, and apoE4, of which the E4 isoform is associated with increased Alzheimer’s disease (AD) risk. Brain glucose hypometabolism, linked to synaptic dysfunction, occurs years before symptom onset in AD, especially in APOEε4-carriers. An association between a higher ratio of plasma apoE4 to apoE3 levels and cerebral glucose hypometabolism was recently discovered in cognitively healthy APOEε3/ε4 subjects. A lower plasma apoE level, regardless of isoform, is linked to increased AD risk. How the plasma apoE level affects neurodegenerative processes in the brain is poorly understood, given that apoE doesn’t cross the blood-brain barrier (BBB). The main aim of this thesis was therefore to investigate a relationship between plasma apoE and features of AD pathophysiology. We explored plasma apoE levels and dimer/monomer formation in APOEε3 and APOEε4 homozygous controls, in patients with mild cognitive impairment (MCI) and AD. In APOEε4-carriers versus non-carriers, plasma apoE levels were lower and significantly correlated with AD biomarkers. ApoE3 homodimers were less in AD patients than in controls. We next examined potential links between plasma apoE, glucose, and insulin levels in the previously examined cognitively healthy APOEε3/ε4 subjects. Lower plasma apoE3 was associated with higher glucose levels in males and subjects with body max index above 25. Plasma glucose levels were negatively correlated with the cerebral metabolic rate of glucose and neuropsychological test scores. To explore the potential effects of a hepatic APOEε4 phenotype on the brain, we compared liver humanized mice with an APOEε4/ε4 versus an APOEε2/ε3 genotype. Mice with an APOEε4/ε4 liver exhibited reduced endogenous mouse apoE in the brain, accompanied by changes in markers of synaptic integrity and insulin signaling. Plasma apoE4 levels were negatively associated with some of the assessed markers. We further explored the effects of a high-fat diet (HFD) in mice with livers humanized with the AD risk-neutral APOEε3/ε3 genotype. Endogenous mouse apoE was increased in the hippocampus following an HFD, with concomitant effects on levels of synaptic markers. In the cortex, we found altered levels of insulin signaling and synaptic markers. Together, our findings indicate that alterations in apoE levels or distribution, hepatic APOEε4 phenotype, and HFD contribute to AD-related pathological processes.Amyloidogenic processing of the amyloid precursor protein (APP) gives rise to Aβ peptides that assemble into the Aβ plaques found in AD. The binding of the adaptor protein Fe65, through its PTB2, to APP might enhance amyloidogenic APP processing. Fe65 is localized both in the cytoplasm and in the nucleus, with compartment-specific biological functions. Mechanisms affecting Fe65 subcellular localization are poorly understood. We explored the impact of the different Fe65 interaction domains WW and PTB2 and APP processing on Fe65 cellular localization. By transfecting Fe65-domain deletion constructs into neuroblastoma cell lines, we found that deleting the PTB2 domain almost abolished nuclear localization. Upon pharmacological inhibition of APP secretases, we found decreased Fe65 localization to the nucleus. To conclude, Fe65-APP interaction and APP processing may be important factors governing the Fe65 cellular localization.
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| 7. |
- Fernández-Calle, Rosalía, et al.
(author)
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APOE in the bullseye of neurodegenerative diseases : impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases
- 2022
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In: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 17:1
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Research review (peer-reviewed)abstract
- ApoE is the major lipid and cholesterol carrier in the CNS. There are three major human polymorphisms, apoE2, apoE3, and apoE4, and the genetic expression of APOE4 is one of the most influential risk factors for the development of late-onset Alzheimer's disease (AD). Neuroinflammation has become the third hallmark of AD, together with Amyloid-β plaques and neurofibrillary tangles of hyperphosphorylated aggregated tau protein. This review aims to broadly and extensively describe the differential aspects concerning apoE. Starting from the evolution of apoE to how APOE's single-nucleotide polymorphisms affect its structure, function, and involvement during health and disease. This review reflects on how APOE's polymorphisms impact critical aspects of AD pathology, such as the neuroinflammatory response, particularly the effect of APOE on astrocytic and microglial function and microglial dynamics, synaptic function, amyloid-β load, tau pathology, autophagy, and cell-cell communication. We discuss influential factors affecting AD pathology combined with the APOE genotype, such as sex, age, diet, physical exercise, current therapies and clinical trials in the AD field. The impact of the APOE genotype in other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies and Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, and multiple sclerosis, is also addressed. Therefore, this review gathers the most relevant findings related to the APOE genotype up to date and its implications on AD and CNS pathologies to provide a deeper understanding of the knowledge in the APOE field.
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| 8. |
- Giannisis,, Andreas, et al.
(author)
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Brain integrity is altered by hepatic APOEε4 in humanized-liver mice
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Other publication (other academic/artistic)abstract
- Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes brain injury and neurodegeneration is unknown. Here we investigated the brains of Fah-/-, Rag2-/-, Il2rg-/- mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation, and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk neurodegenerative diseases.
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| 9. |
- Giannisis, Andreas, et al.
(author)
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Brain integrity is altered by hepatic APOE ε4 in humanized-liver mice
- 2022
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27:8, s. 3533-3543
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Journal article (peer-reviewed)abstract
- Liver-generated plasma apolipoprotein E (apoE) does not enter the brain but nonetheless correlates with Alzheimer’s disease (AD) risk and AD biomarker levels. Carriers of APOEε4, the strongest genetic AD risk factor, exhibit lower plasma apoE and altered brain integrity already at mid-life versus non-APOEε4 carriers. Whether altered plasma liver-derived apoE or specifically an APOEε4 liver phenotype promotes neurodegeneration is unknown. Here we investigated the brains of Fah−/−, Rag2−/−, Il2rg−/− mice on the Non-Obese Diabetic (NOD) background (FRGN) with humanized-livers of an AD risk-associated APOE ε4/ε4 versus an APOE ε2/ε3 genotype. Reduced endogenous mouse apoE levels in the brains of APOE ε4/ε4 liver mice were accompanied by various changes in markers of synaptic integrity, neuroinflammation and insulin signaling. Plasma apoE4 levels were associated with unfavorable changes in several of the assessed markers. These results propose a previously unexplored role of the liver in the APOEε4-associated risk of neurodegenerative disease.
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| 10. |
- Giannisis, Andreas, 1993-
(author)
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Peripheral apolipoprotein E and its emerging role in neurodegenerative disease
- 2023
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Doctoral thesis (other academic/artistic)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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