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Kidney International Feb 2020Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been... (Review)
Review
Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been characterized. ApoE2 homozygote glomerulopathy has been found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages, and occasionally with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, in which non-immune membranous nephropathy-like features were observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure, and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may contribute to the accumulation of lipoproteins in the glomerulus, causing lipoprotein thrombi in LPG.
Topics: Apolipoprotein E2; Apolipoproteins E; Homozygote; Humans; Kidney Diseases; Kidney Glomerulus
PubMed: 31874799
DOI: 10.1016/j.kint.2019.10.031 -
International Journal of Molecular... Aug 2022A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and... (Review)
Review
A preponderance of evidence obtained from genetically modified mice and human population studies reveals the association of apolipoprotein E (apoE) deficiency and polymorphisms with pathogenesis of numerous chronic diseases, including atherosclerosis, obesity/diabetes, and Alzheimer's disease. The human gene is polymorphic with three major alleles, ε2, ε3 and ε4, encoding apoE2, apoE3, and apoE4, respectively. The gene is expressed in many cell types, including hepatocytes, adipocytes, immune cells of the myeloid lineage, vascular smooth muscle cells, and in the brain. ApoE is present in subclasses of plasma lipoproteins, and it mediates the clearance of atherogenic lipoproteins from plasma circulation via its interaction with LDL receptor family proteins and heparan sulfate proteoglycans. Extracellular apoE also interacts with cell surface receptors and confers signaling events for cell regulation, while apoE expressed endogenously in various cell types regulates cell functions via autocrine and paracrine mechanisms. This review article focuses on lipoprotein transport-dependent and -independent mechanisms by which apoE deficiency or polymorphisms contribute to cardiovascular disease, metabolic disease, and neurological disorders.
Topics: Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Atherosclerosis; Cardiovascular Diseases; Humans; Mice; Receptors, LDL
PubMed: 36077289
DOI: 10.3390/ijms23179892 -
Molecular Neurodegeneration Dec 2023Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer's disease (AD). Yet, the cell-specific effects of APOE on microglia function...
Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer's disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.
Topics: Humans; Animals; Mice; Apolipoprotein E4; Microglia; Apolipoprotein E3; Alzheimer Disease; Apolipoproteins E; Mice, Transgenic
PubMed: 38115077
DOI: 10.1186/s13024-023-00693-6 -
Alzheimer's & Dementia : the Journal of... Feb 2024We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological...
INTRODUCTION
We discovered that the APOE3 Christchurch (APOE3Ch) variant may provide resistance to Alzheimer's disease (AD). This resistance may be due to reduced pathological interactions between ApoE3Ch and heparan sulfate proteoglycans (HSPGs).
METHODS
We developed and characterized the binding, structure, and preclinical efficacy of novel antibodies targeting human ApoE-HSPG interactions.
RESULTS
We found that one of these antibodies, called 7C11, preferentially bound ApoE4, a major risk factor for sporadic AD, and disrupts heparin-ApoE4 interactions. We also determined the crystal structure of a Fab fragment of 7C11 and used computer modeling to predict how it would bind to ApoE. When we tested 7C11 in mouse models, we found that it reduced recombinant ApoE-induced tau pathology in the retina of MAPT*P301S mice and curbed pTau S396 phosphorylation in brains of systemically treated APOE4 knock-in mice. Targeting ApoE-HSPG interactions using 7C11 antibody may be a promising approach to developing new therapies for AD.
Topics: Mice; Humans; Animals; Apolipoprotein E4; Heparan Sulfate Proteoglycans; Phosphorylation; Apolipoproteins E; Alzheimer Disease; Immunologic Factors; Apolipoprotein E3
PubMed: 37791598
DOI: 10.1002/alz.13436 -
IUBMB Life Sep 2014Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent... (Review)
Review
Apolipoprotein (apo) E is a 299-residue protein which functions as a key regulator of plasma lipid levels. Human apoE exists as three common isoforms and the parent form, apoE3, operates optimally in promoting clearance of triglyceride (TG)-rich lipoproteins and is associated with normal plasma lipid levels. This result occurs because apoE3 possesses both the requisite lipid-binding ability and affinity for the low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of TG-rich lipoprotein remnant particles. ApoE2 which differs from apoE3 by the single amino acid substitution Arg158Cys located near the LDLR recognition site exhibits impaired binding to the receptor and an inability to promote clearance of TG-rich lipoprotein remnant particles; this isoform is associated with Type-III hyperlipoproteinemia. ApoE4 which differs from apoE3 by the single amino acid substitution Cys112Arg is also associated with dyslipidemia although binding of this isoform to the LDLR is unaffected. The amino acid substitution affects the organization and stability of both the N-terminal helix bundle domain and separately folded C-terminal domain so that apoE4 has enhanced lipid binding ability. As a consequence, apoE4 binds better than apoE3 to the surface of very low density lipoprotein (VLDL) particles and impairs their lipolytic processing in the circulation so that apoE4 is associated with a more pro-atherogenic lipoprotein-cholesterol distribution (higher VLDL-cholesterol/high density lipoprotein-cholesterol ratio). This review summarizes current understanding of the structural differences between apoE2, apoE3, and apoE4, and the molecular mechanisms responsible for the alterations in lipoprotein metabolism resulting from this polymorphism of apoE. Detailed knowledge of how expression of structurally distinct apoE variants modifies lipoprotein metabolism provides a basis for developing ways to manipulate the functionality of apoE in vivo.
Topics: Amino Acid Substitution; Apolipoproteins E; Humans; Lipid Metabolism Disorders; Lipoproteins; Models, Molecular; Protein Binding; Protein Isoforms
PubMed: 25328986
DOI: 10.1002/iub.1314 -
Neurobiology of Aging Jul 2023C-reactive protein (CRP) impacts apolipoprotein E4 (ApoE4) allele to increase Alzheimer's disease (AD) risk. However, it is unclear how the ApoE protein and its binding...
C-reactive protein (CRP) impacts apolipoprotein E4 (ApoE4) allele to increase Alzheimer's disease (AD) risk. However, it is unclear how the ApoE protein and its binding to LRP1 are involved. We found that ApoE2 carriers had the highest but ApoE4 carriers had the lowest concentrations of blood ApoE in both humans and mice; blood ApoE concentration was negatively associated with AD risk. Elevation of peripheral monomeric CRP (mCRP) reduced the expression of ApoE in ApoE2 mice, while it decreased ApoE-LRP1 binding in the brains of ApoE4 mice that was characterized by Proximity Ligation Assay. Both serum ApoE and brain ApoE-LRP1 binding were positively associated with the expression of pericytes that disappeared after mCRP treatment, and negatively associated with brain tauopathy and neuroinflammation in the presence of mCRP. In ApoE mice, mCRP reduced the brain expression levels of synaptophysin and PSD95 and the positive relationship between ApoE-LRP1 binding and synaptophysin or PSD95 expression disappeared. Our study suggests that blood ApoE protects against AD pathogenesis by binding to LRP1 during peripheral chronic inflammation.
Topics: Humans; Mice; Animals; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E4; Synaptophysin; Apolipoproteins E; Brain; Inflammation; Apolipoprotein E3; Low Density Lipoprotein Receptor-Related Protein-1
PubMed: 37060729
DOI: 10.1016/j.neurobiolaging.2023.02.013 -
Biochemical and Biophysical Research... Jan 2024Glaucoma is a chronic blinding eye disease caused by the progressive loss of retinal ganglion cells (RGCs). Currently, no clinically approved treatment can directly... (Review)
Review
Glaucoma is a chronic blinding eye disease caused by the progressive loss of retinal ganglion cells (RGCs). Currently, no clinically approved treatment can directly improve the survival rate of RGCs. The Apolipoprotein E (APOE) gene is closely related to the genetic risk of numerous neurodegenerative diseases and has become a hot topic in the field of neurodegenerative disease research in recent years. The optic nerve and retina are extensions of the brain's nervous system. The pathogenesis of retinal degenerative diseases is closely related to the degenerative diseases of the nerves in the brain. APOE consists of three alleles, ε4, ε3, and ε2, in a single locus. They have varying degrees of risk for glaucoma. APOE4 and the APOE gene deletion (APOE) can reduce RGC loss. By contrast, APOE3 and the overall presence of APOE genes (APOE) result in significant loss of RGC bodies and axons, increasing the risk of glaucoma RGCs death. Currently, there is no clear literature indicating that APOE2 is beneficial or harmful to glaucoma. This study summarises the mechanism of different APOE genes in glaucoma and speculates that APOE targeted intervention may be a promising method for protecting against RGCs loss in glaucoma.
Topics: Humans; Apolipoproteins E; Glaucoma; Neurodegenerative Diseases; Retina; Retinal Degeneration
PubMed: 38145596
DOI: 10.1016/j.bbrc.2023.149414 -
Advances in Experimental Medicine and... 2018Age and apolipoprotein E (ApoE) are the mightiest risk factors for dementia and cardiovascular diseases, but the underlying mechanisms remain unclear. In human, ApoE has... (Review)
Review
Age and apolipoprotein E (ApoE) are the mightiest risk factors for dementia and cardiovascular diseases, but the underlying mechanisms remain unclear. In human, ApoE has three isoforms, ApoE2, ApoE3, and ApoE4, which are expressed by the polymorphic alleles: ɛ2, ɛ3, and ɛ4. Among the three polymorphic alleles, apoE ε4 is the most risk gene. ApoE is the main ligand for the low-density lipoprotein (LDL) receptor and the LDL receptor-related protein (LRP), functioning as the component of plasma lipoproteins in the transportation of lipids. Physiologically, ApoE is a multifunctional protein with central roles in lipid metabolism; it transports lipids, including cholesterol, through the cerebrospinal fluid (CSF) and plasma. ApoE expression regulation and apoE gene polymorphism have an important connection with neurological or neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and other diseases.
Topics: Aging; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Humans; Neurodegenerative Diseases
PubMed: 30232753
DOI: 10.1007/978-981-13-1117-8_5 -
Cancer Research Sep 2023The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of...
UNLABELLED
The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The APOE germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease.
SIGNIFICANCE
APOE germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis-promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes.
Topics: Animals; Humans; Mice; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Carrier Proteins; Melanoma
PubMed: 37335131
DOI: 10.1158/0008-5472.CAN-23-1252 -
International Journal of Molecular... Nov 2018Apoprotein E (apoE) is a multifunctional protein. Its best-characterized function is as a ligand for low-density lipoprotein (LDL) receptor family members to mediate the... (Review)
Review
Apoprotein E (apoE) is a multifunctional protein. Its best-characterized function is as a ligand for low-density lipoprotein (LDL) receptor family members to mediate the clearance of apoB-containing atherogenic lipoproteins. Among its other functions, apoE is involved in cholesterol efflux, especially from cholesterol-loaded macrophage foam cells and other atherosclerosis-relevant cells, and in reverse cholesterol transport. Reverse cholesterol transport is a mechanism by which excess cellular cholesterol is transported via lipoproteins in the plasma to the liver where it can be excreted from the body in the feces. This process is thought to have a role in the attenuation of atherosclerosis. This review summarizes studies on the role of apoE in cellular cholesterol efflux and reverse cholesterol transport and discusses the identification of apoE mimetic peptides that may promote these pathways.
Topics: Animals; Apolipoproteins E; Atherosclerosis; Biological Mimicry; Cholesterol; Hematopoiesis; Hematopoietic Stem Cells; Humans; Macrophages; Protein Binding; Protein Interaction Domains and Motifs
PubMed: 30404132
DOI: 10.3390/ijms19113479