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Neurobiology of Disease May 2020Inheritance of apolipoprotein E4 (APOE4) is a major risk factor for development of Alzheimer's disease (AD). This lipoprotein, in contrast to apoE2, has arginine... (Review)
Review
Inheritance of apolipoprotein E4 (APOE4) is a major risk factor for development of Alzheimer's disease (AD). This lipoprotein, in contrast to apoE2, has arginine residues at positions 112 and 158 in place of cysteines in the latter isoform. In apoE3, the Cys at residue 158 is replaced by an arginine residue. This differential amino acid composition of the three genotypes of APOE have profound influence on the structure, binding properties, and multiple functions of this lipoprotein. Moreover, AD brain is under a high degree of oxidative stress, including that associated with amyloid β-peptide (Aβ) oligomers. Lipid peroxidation produces the highly reactive and neurotoxic molecule, 4-hydroxynonenal (HNE) that forms covalent bonds with cysteine residues (Cys) [as well as with Lys and His residues]. Covalently modified Cys significantly alter structure and function of modified proteins. HNE bound to Cys residue(s) on apoE2 and apoE3 lessens the chance of HNE damage other proteins. apoE4, lacking Cys residues, is unable to scavenge HNE, permitting this latter neurotoxic molecule to lead to oxidative modification of neuronal proteins and eventual cell death. We posit that this lack of HNE scavenging activity in apoE4 significantly contributes to the association of APOE4 inheritance and increased risk of developing AD. Apoe knock-out mice provide insights into the role of this lipoprotein in oxidative stress. Targeted replacement mice in which the mouse gene of Apoe is separately replaced by the human APOE2, APOE3, or APOE4 genes, while keeping the mouse promoter assures the correct location and amount of the human protein isoform. Human APOE targeted replacement mice have been used to investigate the notion that oxidative damage to and death of neurons in AD and its earlier stages is related to APOE genotype. This current paper reviews the intersection of human APOE genotype, oxidative stress, and diminished function of this lipoprotein as a major contributing risk factor for development of AD. Discussion of potential therapeutic strategies to mitigate against the elevated risk of developing AD with inheritance of the APOE4 allele also is presented.
Topics: Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Brain; Cell Death; Humans; Lipid Peroxidation; Mice; Neurons; Oxidative Stress; Protein Isoforms
PubMed: 32036033
DOI: 10.1016/j.nbd.2020.104795 -
Reviews in the Neurosciences Aug 2020Alzheimer's disease (AD) is a very common cause of dementia in the elderly. It is characterized by progressive amnesia and accretions of neurofibrillary tangles (NFTs)... (Review)
Review
Alzheimer's disease (AD) is a very common cause of dementia in the elderly. It is characterized by progressive amnesia and accretions of neurofibrillary tangles (NFTs) of neurons and senile plaques in the neuropil. After aging, the inheritance of the apolipoprotein E (ApoE) epsilon 4 (ε4) allele is the greatest risk factor for late-onset AD. The ApoE protein is the translated product of the ApoE gene. This protein undergoes proteolysis, and the resulting fragments colocalize with neurofibrillary tangles and amyloid plaques, and for that matter may be involved in AD onset and/or progression. Previous studies have reported the pathogenic potential of various ApoE fragments in AD pathophysiology. However, the pathways activated by the fragments are not fully understood. In this review, ApoE fragments obtained from post-mortem brains and body fluids, cerebrospinal fluid (CSF) and plasma, are discussed. Additionally, current knowledge about the process of fragmentation is summarized. Finally, the mechanisms by which these fragments are involved in AD pathogenesis and pathophysiology are discussed.
Topics: Alzheimer Disease; Animals; Apolipoprotein E4; Apolipoproteins E; Brain; Humans; Neurofibrillary Tangles; Plaque, Amyloid
PubMed: 32364519
DOI: 10.1515/revneuro-2019-0115 -
The Journal of Clinical Endocrinology... Aug 2022Lipoprotein(a) (Lp(a)) is a significant cardiovascular risk factor. Knowing the mechanisms that regulate its concentration can facilitate the development of...
BACKGROUND
Lipoprotein(a) (Lp(a)) is a significant cardiovascular risk factor. Knowing the mechanisms that regulate its concentration can facilitate the development of Lp(a)-lowering drugs. This study analyzes the relationship between triglycerides (TGs) and Lp(a) concentrations, cross-sectionally and longitudinally, and the influence of the number and composition of TG-rich lipoproteins, and the APOE genotype.
METHODS
Data from Aragon Workers Health Study (AWHS) (n = 5467), National Health and Nutrition Examination Survey III phase 2 (n = 3860), and Hospital Universitario Miguel Servet (HUMS) (n = 2079) were used for cross-sectional TG and Lp(a) relationship. Lp(a) intrasubject variation was studied in AWHS participants and HUMS patients with repeated measurements. TG-rich lipoproteins were quantified by nuclear magnetic resonance in a subsample from AWHS. Apolipoproteins B and E were quantified by Luminex in very low-density lipoprotein (VLDL) isolated by ultracentrifugation, from HUMS samples. APOE genotyping was carried in AWHS and HUMS participants. Regression models adjusted for age and sex were used to study the association.
RESULTS
The 3 studies showed an inverse relationship between TG and Lp(a). Increased VLDL number, size, and TG content were associated with significantly lower Lp(a). There was an inverse association between the apoE concentration in VLDL and Lp(a). No significant association was observed for apolipoprotein (apo)B. Subjects carrying the apoE2/E2 genotype had significantly lower levels of Lp(a).
CONCLUSION
Our results show an inverse relationship Lp(a)-TG. Subjects with larger VLDL size have lower Lp(a), and lower values of Lp(a) were present in patients with apoE-rich VLDL and apoE2/E2 subjects. Our results suggest that bigger VLDLs and VLDLs enriched in apoE are inversely involved in Lp(a) plasma concentration.
Topics: Apolipoprotein E2; Apolipoproteins B; Apolipoproteins E; Cross-Sectional Studies; Humans; Lipoprotein(a); Lipoproteins, VLDL; Nutrition Surveys; Triglycerides
PubMed: 35789387
DOI: 10.1210/clinem/dgac412 -
The Turkish Journal of Pediatrics 2018Gümüş E, Aras BD, Çilingir O, Yarar C, Çarman KB, Laçiner-Gürlevik S, Koçak O, Artan S. Apolipoprotein E allelic variants and cerebral palsy. Turk J Pediatr...
Gümüş E, Aras BD, Çilingir O, Yarar C, Çarman KB, Laçiner-Gürlevik S, Koçak O, Artan S. Apolipoprotein E allelic variants and cerebral palsy. Turk J Pediatr 2018; 60: 361-371. Cerebral palsy (CP) is the most frequent cause of mobility restriction and posture disturbance in childhood. Against the complexity in disease etiology, genetic factors, including Apolipoprotein E allelic distribution in this patient population, are worthy targets for investigation. ApoE is a lipoprotein of central nervous system encoded by ApoE gene with its 3 main co-dominant alleles, 2, 3 and 4. We aimed to evaluate the allelic frequencies of ApoE gene and its association with coexisting clinical entities such as vision and hearing impairment, cognitive problems, seizures and MRI findings in a pediatric patient population native to middle Anatolian region. Seventy-eight children with CP and 60 healthy controls were genotyped. Genotypic variations along with coexisting clinical conditions and CP-related medical findings were compared between the patient and control groups. The Denver Developmental Screening Test for all, the Wechsler Intelligence Scale for Children-IV (short form WISC-IV; Turkish version) for the patients > 6y and the Stanford-Binet Intelligence Scale (SB-5) for those who aged 2-6 years old were employed to evaluate cognitive and mental abilities of the patients. ApoE 2 and 4 alleles were more frequent in the patient group (p < 0.05), whereas ApoE 3 allele was more frequent in the healthy controls. ApoE 2/4 genotype has been determined 29% in the case group, but none in healthy control group. In the patient group with apolipoprotein 4 or 2 alleles, the rate of emergency cesarean section was found being significantly higher than the group with 3 allele. Brain MRI findings were not significantly different among ApoE allelic variants within the patient group. Our data show that the ApoE alleles may be effective in the development of cerebral palsy and may be associated with some clinical manifestations in those patients.
Topics: Alleles; Apolipoproteins E; Cerebral Palsy; Child; Child, Preschool; Female; Gene Frequency; Genotype; Humans; Magnetic Resonance Imaging; Male; Pregnancy; Turkey
PubMed: 30859759
DOI: 10.24953/turkjped.2018.04.002 -
Translational Psychiatry Mar 2022Post-Traumatic Stress Disorder (PTSD) is a highly prevalent mental health disorder. Due to the high level of variability in susceptibility and severity, PTSD therapies...
Post-Traumatic Stress Disorder (PTSD) is a highly prevalent mental health disorder. Due to the high level of variability in susceptibility and severity, PTSD therapies are still insufficient. In addition to environmental exposures, genetic risks play a prominent role and one such factor is apolipoprotein E. The protein (apoE) is functionally involved in cholesterol transport and metabolism and exists as 3 major isoforms in humans: E2, E3, and E4. To model the role of apolipoprotein E isoform in stress-related changes in behavior and cognition, female and male mice (3-5 months of age) expressing E2, E3, or E4 were used. Mice were either placed into control groups or exposed to chronic variable stress (CVS), which has been shown to induce PTSD-like behavioral and neuroendocrine changes. E2 mice showed a unique response to CVS compared to E3 and E4 mice that included impaired spatial learning and memory, increased adrenal gland weight, and no increase in glucocorticoid receptor protein levels (normalized to apoE levels). In addition, the cholesterol metabolite 7-ketocholesterol was elevated in the cortex after CVS in E3 and E4, but not E2 female mice. E2 confers unique changes in behavioral, cognitive, and biomarker profiles after stress exposure and identify 7-ketocholesterol as a possible novel biomarker of the traumatic stress response. We further explored the relationship between E2 and PTSD in an understudied population by genotyping 102 patients of Cambodian and Vietnamese ethnicity. E2 carriers demonstrated a higher odds ratio of having a PTSD diagnosis compared to E3/E3 carriers, supporting that the E2 genotype is associated with PTSD diagnosis after trauma exposure in this population.
Topics: Animals; Apolipoproteins E; Cholesterol; Female; Genotype; Humans; Male; Mice; Protein Isoforms; Stress Disorders, Post-Traumatic
PubMed: 35347119
DOI: 10.1038/s41398-022-01848-7 -
Frontiers in Bioscience (Elite Edition) Jan 2018Mercury intoxication is a serious public health problem and a worldwide concern. The Minamata Convention on Mercury has been signed by 128 countries and endorsed by the... (Review)
Review
Mercury intoxication is a serious public health problem and a worldwide concern. The Minamata Convention on Mercury has been signed by 128 countries and endorsed by the World Health Organization with the recommendation of promoting the management of epidemiological information. The Central Nervous System is the main target organ for mercury. Symptoms of intoxication include altered motor coordination, visual and tactile dysfunction and paralysis, caused by neurodegeneration with a key role for oxidative damage. Recently, some studies have demonstrated a correlation between mercury intoxication and isoforms of apolipoprotein E (ApoE). In this review, epidemiological data and hypotheses about the possible molecular mechanisms underlying the association between ApoE and mercury intoxication are assessed. Based on the evidence and the neuropathological changes that the presence of ApoE4 and mercury neurotoxicity have in common, we propose a convergent action of both factors. ApoE4 seems to potentiate the damage caused by mercury. Increased knowledge of this interaction using epidemiological and pre-clinical studies is essential to improve prevention strategies to adequately manage intoxicated patients.
Topics: Apolipoproteins E; Humans; Mercury Poisoning; Neurodegenerative Diseases
PubMed: 28930615
DOI: 10.2741/e819 -
Neuroscience Mar 2023Alzheimer's disease (AD) and other neurodegenerative diseases, for which there is no effective cure, cause great social burden. Apolipoprotein E (APOE) is an important... (Review)
Review
Alzheimer's disease (AD) and other neurodegenerative diseases, for which there is no effective cure, cause great social burden. Apolipoprotein E (APOE) is an important lipid transporter, which has been shown to have a close relationship with AD and other neurological disorders in an increasing number of studies, suggesting its potential as a therapeutic target. In this review, we summarize the recent advances in clinical and basic research on the role of APOE in the pathogenesis of multiple neurological diseases, with an emphasis on the new associations between APOE and AD, and between APOE and depression. The progress of APOE research in Parkinson's disease (PD) and some other neurological diseases is briefly discussed.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Neurodegenerative Diseases; Parkinson Disease
PubMed: 36736614
DOI: 10.1016/j.neuroscience.2023.01.032 -
Internal Medicine (Tokyo, Japan) 2023A 32-year-old man was admitted for the evaluation of proteinuria (5.69 g/day). A light microscopic examination showed markedly dilated glomerular capillary loops with...
A 32-year-old man was admitted for the evaluation of proteinuria (5.69 g/day). A light microscopic examination showed markedly dilated glomerular capillary loops with vacuolated areas in many glomeruli, and vacuolated areas were seen on peritubular capillaries in the tubulointerstitium. When electron microscopy specimens prepared by pre-fixation with glutaraldehyde and post-fixation with osmium tetroxide were used for oil red staining, the deposition was confirmed on the affected areas. A genetic analysis of apoE showed that the lipoprotein glomerulopathy was due to apoE-Sendai (Arg145Pro, p.R163P) heterozygosity, which was found in not only the patient but also his mother and twin brother.
Topics: Male; Humans; Adult; Apolipoproteins E; Kidney Diseases; Kidney Glomerulus; Proteinuria; Heterozygote
PubMed: 37532513
DOI: 10.2169/internalmedicine.0834-22 -
Lipids in Health and Disease Aug 2014Excessive energy storage of adipose tissue makes contribution to the occurrence and progression of obesity, which accompanies with multiple adverse complications, such... (Review)
Review
Excessive energy storage of adipose tissue makes contribution to the occurrence and progression of obesity, which accompanies with multiple adverse complications, such as metabolic syndrome, cardiovascular diseases. It is well known that apolipoprotein E, as a component of lipoproteins, performs a key role in maintaining plasma lipoproteins homeostasis. Interestingly, apolipoprotein E is highly expressed in adipocyte and has positive relation with body fat mass. Apolipoprotein E knock-out mice show small fat mass compared to wild type mice. Moreover, adipocyte deficiency in apolipoprotein E shows impaired lipoproeteins internalization and triglyceride accumulation. Apolipopreotein E-deficient lipoproteins can not induce preadipocyte to form round full-lipid adipocyte, whereas apolipoprotein E-containing lipoproteins can. This article mainly reviews the modulation of apolipoprotein E synthesized by adipocyte and apolipoprotein E carried on lipoproteins in adipocyte triglyceride content.
Topics: Adipocytes; Animals; Apolipoproteins E; Humans; Lipoproteins, VLDL; Obesity; Triglycerides
PubMed: 25148848
DOI: 10.1186/1476-511X-13-136 -
American Journal of Respiratory Cell... Aug 2016Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress... (Review)
Review
Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress inflammation, oxidative stress, and tissue remodeling, and to promote adaptive immunity and host defense. Apolipoproteins, such as apolipoprotein E (apoE) and apolipoprotein A-I (apoA-I), are important components of lipoprotein particles that facilitate the transport of cholesterol, triglycerides, and phospholipids between plasma and cells. ApoE-containing lipoprotein particles are internalized into cells by low-density lipoprotein receptors (LDLRs), whereas apoA-I can interact with the ATP-binding cassette subfamily A member 1 (ABCA1) transporter to efflux cholesterol and phospholipids out of cells. ApoE and apoA-I also mediate receptor-independent effects, such as binding to and neutralizing LPS. Both apoE and apoA-I are expressed by lung cells, which allows apoE/LDLR- and apoA-I/ABCA1-dependent pathways to modulate normal lung health and the pathogenesis of respiratory diseases, including asthma, acute lung injury, cancer, emphysema, pulmonary fibrosis, and pulmonary hypertension. Data from human studies and research using experimental murine model systems have shown that both apoE and apoA-I pathways play primarily protective roles in lung biology and respiratory disease. Furthermore, apolipoprotein mimetic peptides, corresponding to the LDLR-binding domain of apoE or the class A amphipathic α-helical structure of apoA-I, have antiinflammatory and antioxidant effects that attenuate the severity of lung disease in murine models. Thus, the development of inhaled apolipoprotein mimetic peptides as a novel treatment paradigm could represent a significant advance for patients with respiratory disease who do not respond to current therapies.
Topics: Animals; Apolipoprotein A-I; Apolipoproteins E; Humans; Lung Diseases
PubMed: 27073971
DOI: 10.1165/rcmb.2016-0060TR