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The European Journal of Neuroscience Nov 2022The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a... (Review)
Review
The APOE gene encoding the Apolipoprotein E protein is the single most significant genetic risk factor for late-onset Alzheimer's disease. The APOE4 genotype confers a significantly increased risk relative to the other two common genotypes APOE3 and APOE2. Intriguingly, APOE4 has been associated with neuropathological and cognitive deficits in the absence of Alzheimer's disease-related amyloid or tau pathology. Here, we review the extensive literature surrounding the impact of APOE genotype on central nervous system dysfunction, focussing on preclinical model systems and comparison of APOE3 and APOE4, given the low global prevalence of APOE2. A multi-hit hypothesis is proposed to explain how APOE4 shifts cerebral physiology towards pathophysiology through interconnected hits. These hits include the following: neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, endosomal trafficking impairments, lipid and cellular metabolism disruption, impaired calcium homeostasis and altered transcriptional regulation. The hits, individually and in combination, leave the APOE4 brain in a vulnerable state where further cumulative insults will exacerbate degeneration and lead to cognitive deficits in the absence of Alzheimer's disease pathology and also a state in which such pathology may more easily take hold. We conclude that current evidence supports an APOE4 multi-hit hypothesis, which contributes to an APOE4 pathophysiological state. We highlight key areas where further study is required to elucidate the complex interplay between these individual mechanisms and downstream consequences, helping to frame the current landscape of existing APOE-centric literature.
Topics: Humans; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E
PubMed: 35510513
DOI: 10.1111/ejn.15685 -
The FEBS Journal Dec 2019Although the interaction of apoE isoforms with amyloid-β (Aβ) peptides plays a critical role in the progression of Alzheimer's disease, how they interact with each...
Although the interaction of apoE isoforms with amyloid-β (Aβ) peptides plays a critical role in the progression of Alzheimer's disease, how they interact with each other remains poorly understood. Here, we investigate the molecular mechanism of apoE-Aβ interactions by comparing the effects of the different domains of apoE on Aβ. The kinetics of aggregation of Aβ1-42 are delayed dramatically in the presence of substoichiometric, nanomolar concentrations of N-terminal fragment (NTF), C-terminal fragment (CTF) and full-length apoE both in lipid-free and in lipidated forms. However, interactions between apoE and Aβ as measured by intermolecular Förster resonance energy transfer (FRET) analysis were found to be minimal at t = 0 but to increase in a time-dependent manner. Thus, apoE must interact with one or more 'intermediates' rather than the monomers of Aβ. Kinetics of FRET between full-length apoE4 labelled with EDANS at position 62 or 139 or 210 or 247 or 276, and tetramethylrhodamine-labelled Aβ (TMR-Aβ), further support an involvement of all the three domains of apoE in the interactions. However, the above-mentioned residues do not appear to form a single pocket in the 3-dimensional structure of apoE. A competitive binding assay examining the effects of unlabelled fragments or full-length apoE on the FRET between EDANS-apoE and TMR-Aβ show that binding affinity of the full-length apoE to Aβ is much higher than that of the fragments. Furthermore, apoE4 is found to interact more strongly than apoE3. We hypothesize that high affinity of the apoE-Aβ interaction is attained due to multivalent binding mediated by multiple interactions between oligomeric Aβ and full-length apoE.
Topics: Amyloid beta-Peptides; Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Fluorescence Resonance Energy Transfer; Humans; Kinetics; Peptide Fragments; Protein Binding
PubMed: 31287614
DOI: 10.1111/febs.14988 -
Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review.Lipids in Health and Disease Jan 2010Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show... (Review)
Review
Apolipoprotein E is a polymorphic and multifunctional protein with numerous roles in lipoprotein metabolism. The three common isoforms apoE2, apoE3 and apoE4 show isoform-specific functional properties including different susceptibilities to diseases. ApoE4 is an accepted risk factor for Alzheimer's disease and cardiovascular disorders. Recently, associations between apoE4 and infectious diseases have been demonstrated. This review summarises how apoE4 may be involved in the infection incidence and associated pathologies of specific infectious diseases, namely hepatitis C, human immunodeficiency virus disease and herpes simplex.ApoE4 seems to be protective against chronic hepatitis C virus infection and retards fibrosis progression. In contrast apoE4 enhances the fusion rate of human immunodeficiency virus with target cell membranes, resulting in accelerated cell entry and faster disease progression. Its association with human immunodeficiency virus-associated dementia remains controversial. Regarding herpes simplex virus infection, apoE4 intensifies virus latency and is associated with increased oxidative damage of the central nervous system, and there is some evidence that herpes simplex virus infection in combination with the apoE4 genotype may be associated with an increased risk of Alzheimer's disease. In addition to reviewing available data from human trials, evidence derived from a variety of cell culture and animal models are considered in this review in order to provide mechanistic insights into observed association between apoE4 genotype and viral disease infection and pathology.
Topics: Adult; Aged; Alleles; Alzheimer Disease; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Female; Genotype; HIV; Hepatitis C; Herpes Simplex; Humans; Male; Middle Aged; Risk
PubMed: 20109174
DOI: 10.1186/1476-511X-9-8 -
Psychosomatic Medicine Apr 2023This study aimed to examine race and apolipoprotein E-e4 allele (APOE-e4) status differences in the longitudinal associations between loneliness and cognitive decline.
OBJECTIVE
This study aimed to examine race and apolipoprotein E-e4 allele (APOE-e4) status differences in the longitudinal associations between loneliness and cognitive decline.
METHODS
The study sample is composed of participants ( N = 7696, 64% Black participants and 36% White participants) from the Chicago Health and Aging Project, a population-based cohort study. Mixed-effects regression models were conducted to examine the longitudinal associations between loneliness on global cognitive function and individual tests of cognitive function. Models were also stratified by race and APOE-e4.
RESULTS
A greater percentage of Black participants (17%) reported loneliness at baseline visit compared with White participants (12%). Black and White participants who were lonely individuals had a similar rate of decline in global cognitive function at 0.075 (95% confidence interval [CI] = -0.082 to -0.068) standard deviation unit (SDU) per year for Black participants and at 0.075 (95% CI = -0.086 to -0.063) SDU per year for White participants. Lonely participants with APOE-e4 had a higher rate of global cognitive decline at -0.102 (95% CI = -0.115 to -0.088) SDU per year than for lonely participants without APOE-e4 at -0.052 (95% CI = -0.059 to -0.045) SDU per year.
CONCLUSIONS
The burden of loneliness and its relation to cognitive decline is higher among participants with APOE-e4 compared with those without APOE-e4. Loneliness is associated with cognitive decline in both Black and White participants.
Topics: Humans; Cohort Studies; Apolipoprotein E4; Alleles; Loneliness; Apolipoproteins E; Cognitive Dysfunction
PubMed: 36626598
DOI: 10.1097/PSY.0000000000001168 -
Cell Reports Aug 2022Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer's disease (sAD). Inflammation is increasingly considered as critical in...
Apolipoprotein E4 (APOEε4) is the major allelic risk factor for late-onset sporadic Alzheimer's disease (sAD). Inflammation is increasingly considered as critical in sAD initiation and progression. Identifying brain molecular mechanisms that could bridge these two risk factors remain unelucidated. Leveraging induced pluripotent stem cell (iPSC)-based strategies, we demonstrate that APOE controls inflammation in human astrocytes by regulating Transgelin 3 (TAGLN3) expression and, ultimately, nuclear factor κB (NF-κB) activation. We uncover that APOE4 specifically downregulates TAGLN3, involving histone deacetylases activity, which results in low-grade chronic inflammation and hyperactivated inflammatory responses. We show that APOE4 exerts a dominant negative effect to prime astrocytes toward a pro-inflammatory state that is pharmacologically reversible by TAGLN3 supplementation. We further confirm that TAGLN3 is downregulated in the brain of patients with sAD. Our findings highlight the APOE-TAGLN3-NF-κB axis regulating neuroinflammation in human astrocytes and reveal TAGLN3 as a molecular target to modulate neuroinflammation, as well as a potential biomarker for AD.
Topics: Alzheimer Disease; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Astrocytes; Humans; Inflammation; NF-kappa B; Nerve Tissue Proteins
PubMed: 35977506
DOI: 10.1016/j.celrep.2022.111200 -
Nutrients Jun 2022Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system....
Apolipoprotein E (apoE) occurs on the majority of plasma lipoproteins and plays a major role in the lipid metabolism in the periphery and in the central nervous system. ApoE is a polymorphic protein with three common isoforms, apoE2, apoE3 and apoE4, derived from respective alleles ε2, ε3 and ε4. The aim of this study was to develop a sample pretreatment protocol combined with rapid mass spectrometry (MS)-based assay for simultaneous apolipoprotein profiling and apoE phenotype identification. This assay was validated in 481 samples from patients with stable atherosclerotic cardiovascular disease (ASCVD) and applied to study association with mild cognitive impairment (MCI) in the LIFE Adult study, including overall 690 study subjects. Simultaneous quantification of 8−12 major apolipoproteins including apoA-I, apoB-100 and apoE could be performed within 6.5 min. Phenotyping determined with the developed MS assay had good agreement with the genotyping by real-time fluorescence PCR (97.5%). ApoE2 isoform was associated with the highest total apoE concentration compared to apoE3 and apoE4 (p < 0.001). In the subgroup of diabetic atherosclerotic cardiovascular disease (ASCVD) patients, apoE2 isoform was related to higher apoC-I levels (apoE2 vs. apoE3, p < 0.05), while in the subgroup of ASCVD patients under statin therapy apoE2 was related to lower apoB-100 levels (apoE2 vs. apoE3/apoE4, p < 0.05). A significant difference in apoE concentration observed between mild cognitive impairment (MCI) subjects and controls was confirmed for each apoE phenotype. In conclusion, this study provides evidence for the successful implementation of an MS-based apoE phenotyping assay, which can be used to assess phenotype effects on plasma lipid and apolipoprotein levels.
Topics: Apolipoprotein B-100; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Cardiovascular Diseases; Cognitive Dysfunction; Humans; Mass Spectrometry; Protein Isoforms
PubMed: 35745204
DOI: 10.3390/nu14122474 -
The FEBS Journal Oct 2009Apolipoprotein E is a polymorphic glycoprotein in humans with a molecular mass of 34.5 kDa. It is a component of chylomicron remnants, very low density lipoprotein, low... (Review)
Review
Apolipoprotein E is a polymorphic glycoprotein in humans with a molecular mass of 34.5 kDa. It is a component of chylomicron remnants, very low density lipoprotein, low density lipoprotein and high density lipoprotein, and is primarily responsible for maintaining plasma lipid homeostasis. In addition to these well-documented functions, recent studies in experimental mouse models, as well as population studies, show that apolipoprotein E also plays an important role in the development of obesity and insulin resistance. It is widely accepted that disruption in homeostasis between food intake and energy expenditure, and the subsequent deposition of excess fatty acids into fat cells in the form of triglycerides, leads to the development of obesity. Despite the pivotal role of obesity and dyslipidemia in the development of the metabolic syndrome and heart disease, the functional interactions between adipose tissue and components of the lipoprotein transport system have not yet been investigated thoroughly. In this minireview, we focus on the current literature pertinent to the involvement of apolipoprotein E in the development of pathologies associated with the metabolic syndrome.
Topics: Animals; Apolipoproteins E; Humans; Insulin Resistance; Mice; Obesity
PubMed: 19754875
DOI: 10.1111/j.1742-4658.2009.07301.x -
Proceedings of the National Academy of... Feb 2023The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart...
The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein.
Topics: Apolipoprotein E4; Apolipoprotein E3; Apolipoprotein E2; Apolipoproteins E; Protein Conformation; Protein Isoforms
PubMed: 36749730
DOI: 10.1073/pnas.2215371120 -
Human & Experimental Toxicology 2022Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and...
Anesthesia may induce neuronal tau phosphorylation and neurotoxicity in the developing brain. Apolipoprotein E (ApoE) may play a protective role in neuronal activity and injury repair, whereas its 18-kDa fragments are reported to induce neurodegeneration and neuroinflammation in Alzheimer's disease patients. We aimed to test the hypothesis that differences in 18-kDa ApoE fragment levels, but not full-length ApoE, in primary neurons contribute to differences in tau phosphorylation and neuroinflammation with or without sevoflurane administration. Neurons extracted from wild-type (WT), ApoE knockout (ApoE-KO), and ApoE ε3-and ε2-targeted replacement (ApoE ε3, ApoE ε2) mice were divided into control and sevoflurane groups. Neurons in the sevoflurane group were treated with 21% O, 5% CO, and 4.1% sevoflurane, whereas those in the control group were treated with 21% O and 5% CO only on day 5 of neuronal culture. ApoE mRNA, full-length ApoE, 18-kDa ApoE fragments, Tau-PS202/PT205 (AT8), Tau-PSer396/404 (PHF1), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 and IL-1β levels were measured. The data showed that sevoflurane-induced AT8 and PHF1 increases, and TNF-α, IL-6, and IL-1β increases in WT or ApoE ε3 neurons (both expressing full-length and 18-kDa fragmented ApoE) could be mitigated in ApoE ε2 (only expressing full-length ApoE), but not in ApoE-KO neurons, indicating that differences in 18-kDa ApoE fragments, but not full-length ApoE, in primary mouse neurons contributed to differences in tau phosphorylation and neuroinflammation with or without 4.1% sevoflurane administration.
Topics: Anesthetics; Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoproteins E; Carbon Dioxide; Humans; Interleukin-6; Mice; Neuroinflammatory Diseases; Neurotoxicity Syndromes; Phosphorylation; Sevoflurane; Tumor Necrosis Factor-alpha
PubMed: 35575159
DOI: 10.1177/09603271221102519 -
Scientific Reports Feb 2022Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously,... (Comparative Study)
Comparative Study
Apolipoprotein E (APOE) alleles impact pathogenesis and risk for multiple human diseases, making them primary targets for disease treatment and prevention. Previously, we and others reported an association between APOE alleles and the gut microbiome. Here, we evaluated effects of APOE heterozygosity and tested whether these overall results extended to mice maintained under ideal conditions for microbiome analyses. To model human APOE alleles, this study used APOE targeted replacement (TR) mice on a C57Bl/6 background. To minimize genetic drift, homozygous APOE3 mice were crossed to homozygous APOE2 or homozygous APOE4 mice prior to the study, and the resulting heterozygous progeny crossed further to generate the study mice. To maximize environmental homogeneity, mice with mixed genotypes were housed together and used bedding from the cages was mixed and added back as a portion of new bedding. Fecal samples were obtained from mice at 3-, 5- and 7-months of age, and microbiota analyzed by 16S ribosomal RNA gene amplicon sequencing. Linear discriminant analysis of effect size (LefSe) identified taxa associated with APOE status, depicted as cladograms to show phylogenetic relatedness. The influence of APOE status was tested on alpha-diversity (Shannon H index) and beta-diversity (principal coordinate analyses and PERMANOVA). Individual taxa associated with APOE status were identified by classical univariate analysis. Whether findings in the APOE mice were replicated in humans was evaluated by using published microbiome genome wide association data. Cladograms revealed robust differences with APOE in male mice and limited differences in female mice. The richness and evenness (alpha-diversity) and microbial community composition (beta-diversity) of the fecal microbiome was robustly associated with APOE status in male but not female mice. Classical univariate analysis revealed individual taxa that were significantly increased or decreased with APOE, illustrating a stepwise APOE2-APOE3-APOE4 pattern of association with heterozygous animals trending as intermediate in the stepwise pattern. The relative abundance of bacteria from the class Clostridia, order Clostridiales, family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of Erysipelotrichia increased with APOE4 status, a finding that extended to humans. In this study, wherein mice were maintained in an ideal fashion for microbiome studies, gut microbiome profiles were strongly and significantly associated with APOE status in male APOE-TR mice. Erysipelotrichia are increased with APOE4 in both mice and humans. APOE allelic effects appeared generally intermediate in heterozygous animals. Further evaluation of these findings in humans, as well as studies evaluating the impact of the APOE-associated microbiota on disease-relevant phenotypes, will be necessary to determine if alterations in the gut microbiome represent a novel mechanism whereby APOE alleles impact disease.
Topics: Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Bacteria; Dysbiosis; Feces; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Genes, Dominant; Genes, Recessive; Heterozygote; Homozygote; Humans; Male; Mice, Inbred C57BL; Mice, Knockout, ApoE; Phenotype; Ribotyping; Sex Factors; Mice
PubMed: 35115575
DOI: 10.1038/s41598-022-05763-1