RESUMEN

OBJECTIVE: Apolipoprotein E (APOE) gene polymorphisms were associated with coronary atherosclerosis and hypertension. However, the relationship between APOE polymorphisms and coronary atherosclerosis susceptibility in hypertensive patients is unclear. The aim of this study was to assess the relationship. METHODS: A total of 1713 patients with hypertension who were admitted to Meizhou People's Hospital from November 2019 to August 2023 were retrospectively analyzed, including 848 patients with coronary atherosclerosis and 865 patients without coronary atherosclerosis. The rs429358 and rs7412 polymorphisms of APOE were genotyped, and relationship between APOE polymorphisms and the risk of coronary atherosclerosis in hypertensive patients were analyzed. RESULTS: There were 10 (0.6%), 193 (11.3%), 30 (1.8%), 1234 (72.0%), 233 (13.6%), and 13 (0.8%) individuals with APOE ɛ2/ɛ2, ɛ2/ɛ3, ɛ2/ɛ4, ɛ3/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4 genotype, respectively. The frequency of APOE ɛ3/ɛ4 was higher (16.4% vs. 10.9%, p = 0.001) in the patients with coronary atherosclerosis than controls. Logistic analysis showed that body mass index (BMI) ≥ 24.0 kg/m2 (24.0 kg/m2 vs. 18.5-23.9 kg/m2, odds ratio (OR): 1.361, 95% confidence interval (CI): 1.112-1.666, p = 0.003), advanced age (≥ 65/<65, OR:1.303, 95% CI: 1.060-1.602, p = 0.012), history of smoking (OR: 1.830, 95% CI: 1.379-2.428, p < 0.001), diabetes mellitus (OR: 1.380, 95% CI: 1.119-1.702, p = 0.003), hyperlipidemia (OR: 1.773, 95% CI: 1.392-2.258, p < 0.001), and APOE ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 1.514, 95% CI: 1.133-2.024, p = 0.005) were associated with coronary atherosclerosis in hypertensive patients. CONCLUSIONS: Overweight (BMI ≥ 24.0 kg/m2), advanced age, history of smoking, diabetes mellitus, and APOE ɛ3/ɛ4 genotype were independent risk factors for coronary atherosclerosis in hypertensive patients.

Asunto(s)

Apolipoproteína E3 , Apolipoproteína E4 , Enfermedad de la Arteria Coronaria , Predisposición Genética a la Enfermedad , Hipertensión , Humanos , Masculino , Femenino , Enfermedad de la Arteria Coronaria/genética , Persona de Mediana Edad , Hipertensión/genética , Hipertensión/epidemiología , Hipertensión/diagnóstico , Estudios Retrospectivos , Medición de Riesgo , Anciano , Factores de Riesgo , Apolipoproteína E3/genética , Apolipoproteína E4/genética , China/epidemiología , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios de Asociación Genética , Apolipoproteínas E

RESUMEN

Therapeutics enhancing apolipoprotein (APOE) positive function are a priority, because APOE4 is the major genetic risk factor for Alzheimer's disease (AD). The function of APOE, the key constituent of lipoprotein particles that transport cholesterol and lipids in the brain, is dependent on lipidation by ABCA1, a cell-membrane cholesterol transporter. ABCA1 transcription is regulated by liver X receptors (LXR): agonists have been shown to increase ABCA1, often accompanied by unwanted lipogenesis and elevated triglycerides (TG). Therefore, nonlipogenic ABCA1-inducers (NLAI) are needed. Two rounds of optimization of an HTS hit, derived from a phenotypic screen, gave lead compound 39 that was validated and tested in E3/4FAD mice that express human APOE3/4 and five mutant APP and PSEN1 human transgenes. Treatment with 39 increased ABCA1 expression, enhanced APOE lipidation, and reversed multiple AD phenotypes, without increasing TG. This NLAI/LXR-agonist study is the first in a human APOE-expressing model with hallmark amyloid-ß pathology.

Asunto(s)

Transportador 1 de Casete de Unión a ATP , Enfermedad de Alzheimer , Apolipoproteína E3 , Apolipoproteína E4 , Modelos Animales de Enfermedad , Ratones Transgénicos , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Humanos , Ratones , Apolipoproteína E4/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Receptores X del Hígado/agonistas , Receptores X del Hígado/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo

RESUMEN

BACKGROUND: Apolipoprotein E (ApoE) plays a major role in lipid homeostasis and myelination in the central nervous system. Although ApoE gene variants have been linked with cognitive impairment in the setting of Multiple sclerosis (MS), no association with disease susceptibility was found, while similar studies in pediatric-onset MS (POMS) are limited. OBJECTIVE: This study aims to explore the role of ApoE gene variants in the POMS susceptibility of a Hellenic cohort and any association with disease features. METHODS: 112 POMS, fulfilling the revised IPMSSG 2013 criteria, 391 adult-onset MS (AOMS) and 200 healthy controls (HCs), were enrolled. After DNA extraction, ApoE genotyping was performed by a polymerase chain reaction and sequence-specific-oligonucleotide technique. RESULTS: ApoE2/E3 genotype and ApoE2 allele were found to be significantly more frequent among POMS patients compared to HCs [(20.5% vs 11 %, OR [95 %]: 2.1 (1.1-4.0), p = 0.03)], and [(11% vs 5.3 %, OR [95 %]: 2.3 (1.2-4.1), p = 0.01)], respectively. Additionally, significantly lower frequencies of the ApoE3/E3 genotype and the ApoE3 allele were observed in POMS patients compared to HCs (59.8% vs 79 %, OR [95 %]:0.40 (0.24-0.65), p = 0.0005 and 79% vs 89 % 0.46, OR [95 %]: (0.30-0.73), p = 0.001)], respectively. CONCLUSIONS: The ApoE2 allele may represent a novel risk factor for POMS development.

Asunto(s)

Apolipoproteínas E , Predisposición Genética a la Enfermedad , Esclerosis Múltiple , Humanos , Masculino , Femenino , Esclerosis Múltiple/genética , Adulto , Apolipoproteínas E/genética , Adolescente , Niño , Grecia , Adulto Joven , Edad de Inicio , Estudios de Cohortes , Apolipoproteína E2/genética , Apolipoproteína E3/genética

RESUMEN

There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer's disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.

Asunto(s)

Administración Intranasal , Encéfalo , Cognición , Dieta Alta en Grasa , Insulina , Animales , Femenino , Masculino , Insulina/metabolismo , Dieta Alta en Grasa/efectos adversos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Ratones , Humanos , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Ratones Transgénicos , Enfermedad de Alzheimer/metabolismo , Modelos Animales de Enfermedad

RESUMEN

Apolipoprotein-E4 (ApoE4) is an important genetic risk factor for Alzheimer's disease. The development of targeted-replacement human ApoE knock-in mice facilitates research into mechanisms by which ApoE4 affects the brain. We performed meta-analyses and meta-regression analyses to examine differences in cognitive performance between ApoE4 and ApoE3 mice. We included 61 studies in which at least one of the following tests was assessed: Morris Water Maze (MWM), novel object location (NL), novel object recognition (NO) and Fear Conditioning (FC) test. ApoE4 vs. ApoE3 mice performed significantly worse on the MWM (several outcomes, 0.17 ≤ g ≤ 0.60), NO (exploration, g=0.33; index, g=0.44) and FC (contextual, g=0.49). ApoE4 vs. ApoE3 differences were not systematically related to sex or age. We conclude that ApoE4 knock-in mice in a non-AD condition show some, but limited cognitive deficits, regardless of sex and age. These effects suggest an intrinsic vulnerability in ApoE4 mice that may become more pronounced under additional brain load, as seen in neurodegenerative diseases.

Asunto(s)

Apolipoproteína E4 , Disfunción Cognitiva , Técnicas de Sustitución del Gen , Animales , Apolipoproteína E4/genética , Ratones , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Humanos , Ratones Transgénicos , Modelos Animales de Enfermedad , Apolipoproteína E3/genética

RESUMEN

Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer's disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage. We investigated the relationship between APOE genotypes and fertility in EFAD mice, a transgenic mouse model expressing h-APOE. We show that APOE4 transgenic mice had the highest level of reproductive performance, followed by APOE3 and APOE2. Intriguingly, APOE3 pregnancies had more fetal resorptions and reduced fetal weights relative to APOE4 pregnancies. In conclusion, APOE genotypes impact fertility and pregnancy outcomes in female mice, in concordance with findings in human populations. These mouse models may help elucidate how h-APOE4 promotes reproductive fitness at the cost of AD in later life.

Asunto(s)

Enfermedad de Alzheimer , Apolipoproteínas E , Modelos Animales de Enfermedad , Fertilidad , Ratones Transgénicos , Animales , Femenino , Humanos , Ratones , Embarazo , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Fertilidad/genética , Genotipo , Polimorfismo Genético

RESUMEN

OBJECTIVE: Dyslipidemia is one of the causes of coronary heart disease (CAD), and apolipoprotein E (APOE) gene polymorphism affects lipid levels. However, the relationship between APOE gene polymorphisms and premature CAD (PCAD, male CAD patients with ≤ 55 years old and female with ≤ 65 years old) risk had different results in different studies. The aim of this study was to assess this relationship and to further evaluate the relationship between APOE gene polymorphisms and PCAD risk in the Hakka population. METHODS: This study retrospectively analyzed 301 PCAD patients and 402 age matched controls without CAD. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) -chip technique. The distribution of APOE genotypes and alleles between the case group and the control group was compared. The relationship between APOE genotypes and PCAD risk was obtained by logistic regression analysis. RESULTS: The frequency of the APOE ɛ3/ɛ4 genotype (18.9% vs. 10.2%, p = 0.001) and ε4 allele (11.1% vs. 7.0%, p = 0.007) was higher in the PCAD patients than that in controls, respectively. PCAD patients with ɛ2 allele had higher TG level than those with ɛ3 allele, and controls carried ɛ2 allele had higher HDL-C level and lower LDL-C level than those carried ɛ3 allele. Regression logistic analysis showed that BMI ≥ 24.0 kg/m2 (BMI ≥ 24.0 kg/m2 vs. BMI 18.5-23.9 kg/m2, OR: 1.763, 95% CI: 1.235-2.516, p = 0.002), history of smoking (Yes vs. No, OR: 5.098, 95% CI: 2.910-8.930, p < 0.001), ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 2.203, 95% CI: 1.363-3.559, p = 0.001), ε4 allele (ε4 vs. ε3, OR: 2.125, 95% CI: 1.333-3.389, p = 0.002), and TC level (OR: 1.397, 95% CI: 1.023-1.910, p = 0.036) were associated with PCAD. CONCLUSIONS: In summary, BMI ≥ 24.0 kg/m2, history of smoking, APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD. It means that young individuals who are overweight, have a history of smoking, and carried APOE ɛ3/ɛ4 genotype had increased risk of PCAD.

Asunto(s)

Apolipoproteína E3 , Apolipoproteína E4 , Enfermedad de la Arteria Coronaria , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Enfermedad de la Arteria Coronaria/genética , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Factores de Riesgo , Adulto , Fenotipo , Medición de Riesgo , Dislipidemias/genética , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Polimorfismo de Nucleótido Simple , Anciano , Estudios de Casos y Controles , Genotipo , Apolipoproteínas E

RESUMEN

BACKGROUND: Variants in APOE and PSEN1 (encoding apolipoprotein E and presenilin 1, respectively) alter the risk of Alzheimer's disease. We previously reported a delay of cognitive impairment in a person with autosomal dominant Alzheimer's disease caused by the PSEN1 E280A variant who also had two copies of the apolipoprotein E3 Christchurch variant (APOE3 Ch). Heterozygosity for the APOE3 Ch variant may influence the age at which the onset of cognitive impairment occurs. We assessed this hypothesis in a population in which the PSEN1 E280A variant is prevalent. METHODS: We analyzed data from 27 participants with one copy of the APOE3 Ch variant among 1077 carriers of the PSEN1 E280A variant in a kindred from Antioquia, Colombia, to estimate the age at the onset of cognitive impairment and dementia in this group as compared with persons without the APOE3 Ch variant. Two participants underwent brain imaging, and autopsy was performed in four participants. RESULTS: Among carriers of PSEN1 E280A who were heterozygous for the APOE3 Ch variant, the median age at the onset of cognitive impairment was 52 years (95% confidence interval [CI], 51 to 58), in contrast to a matched group of PSEN1 E280A carriers without the APOE3 Ch variant, among whom the median age at the onset was 47 years (95% CI, 47 to 49). In two participants with the APOE3 Ch and PSEN1 E280A variants who underwent brain imaging, 18F-fluorodeoxyglucose positron-emission tomographic (PET) imaging showed relatively preserved metabolic activity in areas typically involved in Alzheimer's disease. In one of these participants, who underwent 18F-flortaucipir PET imaging, tau findings were limited as compared with persons with PSEN1 E280A in whom cognitive impairment occurred at the typical age in this kindred. Four studies of autopsy material obtained from persons with the APOE3 Ch and PSEN1 E280A variants showed fewer vascular amyloid pathologic features than were seen in material obtained from persons who had the PSEN1 E280A variant but not the APOE3 Ch variant. CONCLUSIONS: Clinical data supported a delayed onset of cognitive impairment in persons who were heterozygous for the APOE3 Ch variant in a kindred with a high prevalence of autosomal dominant Alzheimer's disease. (Funded by Good Ventures and others.).

Asunto(s)

Enfermedad de Alzheimer , Apolipoproteína E3 , Presenilina-1 , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Edad de Inicio , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E3/genética , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Colombia , Familia , Genes Dominantes , Heterocigoto , Tomografía de Emisión de Positrones , Presenilina-1/genética , Estudios Retrospectivos

RESUMEN

BACKGROUND: Individuals with Alzheimer's disease (AD) often require many medications; however, these medications are dosed using regimens recommended for individuals without AD. This is despite reduced abundance and function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in AD, which can impact brain exposure of drugs. The fundamental mechanisms leading to reduced P-gp abundance in sporadic AD remain unknown; however, it is known that the apolipoprotein E (apoE) gene has the strongest genetic link to sporadic AD development, and apoE isoforms can differentially alter BBB function. The aim of this study was to assess if apoE affects P-gp abundance and function in an isoform-dependent manner using a human cerebral microvascular endothelial cell (hCMEC/D3) model. METHODS: This study assessed the impact of apoE isoforms on P-gp abundance (by western blot) and function (by rhodamine 123 (R123) uptake) in hCMEC/D3 cells. Cells were exposed to recombinant apoE3 and apoE4 at 2 - 10 µg/mL over 24 - 72 hours. hCMEC/D3 cells were also exposed for 72 hours to astrocyte-conditioned media (ACM) from astrocytes expressing humanised apoE isoforms. RESULTS: P-gp abundance in hCMEC/D3 cells was not altered by recombinant apoE4 relative to recombinant apoE3, nor did ACM containing human apoE isoforms alter P-gp abundance. R123 accumulation in hCMEC/D3 cells was also unchanged with recombinant apoE isoform treatments, suggesting no change to P-gp function, despite both abundance and function being altered by positive controls SR12813 (5 µM) and PSC 833 (5 µM), respectively. CONCLUSIONS: Different apoE isoforms have no direct influence on P-gp abundance or function within this model, and further in vivo studies would be required to address whether P-gp abundance or function are reduced in sporadic AD in an apoE isoform-specific manner.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Barrera Hematoencefálica , Encéfalo , Células Endoteliales , Isoformas de Proteínas , Humanos , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E3/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E4/genética , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/irrigación sanguínea , Línea Celular , Medios de Cultivo Condicionados/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Microvasos/metabolismo , Microvasos/citología , Isoformas de Proteínas/metabolismo , Rodamina 123/metabolismo

RESUMEN

Coronavirus disease 2019 (COVID-19) was initially considered a primarily respiratory disease but is now known to affect other organs including the heart and brain. A major route by which COVID-19 impacts different organs is via the vascular system. We studied the impact of apolipoprotein E (APOE) genotype and inflammation on vascular infectivity by pseudo-typed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses in mouse and human cultured endothelial cells and pericytes. Possessing the APOE4 allele or having existing systemic inflammation is known to enhance the severity of COVID-19. Using targeted replacement human APOE3 and APOE4 mice and inflammation induced by bacterial lipopolysaccharide (LPS), we investigated infection by SARS-CoV-2. Here, we show that infectivity was higher in murine cerebrovascular pericytes compared to endothelial cells and higher in cultures expressing APOE4. Furthermore, increasing the inflammatory state of the cells by prior incubation with LPS increased infectivity into human and mouse pericytes and human endothelial cells. Our findings provide insights into the mechanisms underlying severe COVID-19 infection, highlighting how risk factors such as APOE4 genotype and prior inflammation may exacerbate disease severity by augmenting the virus's ability to infect vascular cells.

Asunto(s)

COVID-19 , Células Endoteliales , Pericitos , SARS-CoV-2 , Pericitos/virología , Pericitos/metabolismo , Pericitos/patología , Humanos , Animales , SARS-CoV-2/fisiología , SARS-CoV-2/patogenicidad , COVID-19/virología , COVID-19/patología , Ratones , Células Endoteliales/virología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Factores de Riesgo , Lipopolisacáridos/farmacología , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Inflamación/virología , Inflamación/patología

RESUMEN

The apolipoprotein E (APOE) gene has been studied due to its influence on Alzheimer's disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often copresent with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence of APOE genotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of APOE3 or APOE4 influences ventilation during baseline breathing (normoxia) and during respiratory challenges. We show that sex and APOE genotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. In addition, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.NEW & NOTEWORTHY This study is the first to use whole body plethysmography (WBP) to measure the impact of APOE alleles on breathing under normoxia and during adverse respiratory challenges in a targeted replacement Alzheimer's model. Both sex and genotype were shown to affect breathing under normoxia, hypoxic challenge, and hypoxic-hypercapnic challenge. This work has important implications regarding the impact of genetics on respiratory control as well as applications pertaining to conditions of disordered breathing including sleep apnea and neurotrauma.

Asunto(s)

Hipoxia , Animales , Femenino , Masculino , Ratones , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genotipo , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Ratones Endogámicos C57BL , Ratones Transgénicos , Respiración , Caracteres Sexuales , Factores Sexuales

RESUMEN

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

Asunto(s)

Enfermedad de Alzheimer , Apolipoproteína E4 , Biomarcadores , Homocigoto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Edad de Inicio , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/líquido cefalorraquídeo , Amiloide/metabolismo , Amiloide/genética , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Tomografía de Emisión de Positrones , Proteínas tau/genética , Proteínas tau/líquido cefalorraquídeo

RESUMEN

The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer's disease risk: the APOE4 allele increases risk, while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in the brain of humans and mice. We hypothesized that the protective effects of APOE2 are, in part, mediated through the endosomal pathway. Messenger RNA analyses showed that APOE2 leads to an enrichment of endosomal pathways in the brain when compared with both APOE3 and APOE4. Moreover, we show age-dependent alterations in the recruitment of key endosomal regulatory proteins to vesicle compartments when comparing APOE2 to APOE3. In contrast to the early endosome enlargement previously shown in Alzheimer's disease and APOE4 models, we detected similar morphology and abundance of early endosomes and retromer-associated vesicles within cortical neurons of aged APOE2 targeted-replacement mice compared with APOE3. Additionally, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, consistent with enhanced endosomal cargo clearance by exosomes to the extracellular space. Our findings thus demonstrate that APOE2 enhances an endosomal clearance pathway, which has been shown to be impaired by APOE4 and which may be protective due to APOE2 expression during brain aging.

Asunto(s)

Envejecimiento , Apolipoproteína E2 , Encéfalo , Endosomas , Exosomas , Animales , Humanos , Ratones , Envejecimiento/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Apolipoproteína E2/metabolismo , Apolipoproteína E2/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E4/metabolismo , Apolipoproteína E4/genética , Encéfalo/metabolismo , Endosomas/metabolismo , Exosomas/metabolismo , Ratones Endogámicos C57BL , Neuronas/metabolismo

RESUMEN

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E2). However, clinical data are conflicting on whether E2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aß42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E2 for 4 months. In E3FAD mice, we found that E2 mitigated the detrimental effect of ovariectomy on memory, with no effect on Aß in the early paradigm and only improved learning in the late paradigm. Although E2 lowered Aß in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher Aß pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and Aß pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of Aß pathology, APOE impacts the response to E2 supplementation post-menopause.

Asunto(s)

Apolipoproteína E3 , Apolipoproteína E4 , Estradiol , Ovariectomía , Animales , Femenino , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Estradiol/farmacología , Ratones Transgénicos

Asunto(s)

Enfermedad de Alzheimer , Apolipoproteína E4 , Humanos , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Genotipo , Anciano , Amiloide/análisis , Líquido Cefalorraquídeo/química , Química Encefálica , Anciano de 80 o más Años , Apolipoproteína E3/genética , Predisposición Genética a la Enfermedad/genética

RESUMEN

Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human-induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.

Asunto(s)

Astrocitos , Células Madre Pluripotentes Inducidas , Proteínas tau , Astrocitos/metabolismo , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Femenino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteína E3/genética , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Células Cultivadas , Técnicas de Cocultivo

RESUMEN

BACKGROUND: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. METHODS: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit ß5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit ß1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. RESULTS: ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. CONCLUSIONS: We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.

Asunto(s)

Tejido Adiposo Blanco , Aterosclerosis , Modelos Animales de Enfermedad , Síndrome Metabólico , Ratones Endogámicos C57BL , Complejo de la Endopetidasa Proteasomal , Receptores de LDL , Animales , Aterosclerosis/patología , Aterosclerosis/prevención & control , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/inmunología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/patología , Receptores de LDL/genética , Receptores de LDL/deficiencia , Complejo de la Endopetidasa Proteasomal/metabolismo , Masculino , Inhibidores de Proteasoma/farmacología , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Enfermedades de la Aorta/prevención & control , Enfermedades de la Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/enzimología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Placa Aterosclerótica , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones Noqueados para ApoE , Ratones , Metabolismo Energético/efectos de los fármacos , Oligopéptidos

RESUMEN

OBJECTIVE: Obesity is the top modifiable risk factor for Alzheimer's disease. We hypothesized that high fat diet (HFD)-induced obesity alters brain transcriptomics in APOE-genotype and sex dependent manners. Here, we investigated interactions between HFD, APOE, and sex, using a knock-in mouse model of the human APOE3 and APOE4 alleles. METHODS: Six-month-old APOE3-TR and APOE4-TR mice were treated with either HFD or control chow. After 4 months, total RNA was extracted from the cerebral cortices and analyzed by poly-A enriched RNA sequencing on the Illumina platform. RESULTS: Female mice demonstrated profound HFD-induced transcriptomic changes while there was little to no effect in males. In females, APOE3 brains demonstrated about five times more HFD-induced transcriptomic changes (399 up-regulated and 107 down-regulated genes) compared to APOE4 brains (30 up-regulated and 60 down-regulated). Unsupervised clustering analysis revealed two gene sets that responded to HFD in APOE3 mice but not in APOE4 mice. Pathway analysis demonstrated that HFD in APOE3 mice affected cortical pathways related to feeding behavior, blood circulation, circadian rhythms, extracellular matrix, and cell adhesion. CONCLUSIONS: Female mice and APOE3 mice have the strongest cortical transcriptomic responses to HFD related to feeding behavior and extracellular matrix remodeling. The relative lack of response of the APOE4 brain to stress associated with obesity may leave it more susceptible to additional stresses that occur with aging and in AD.

Asunto(s)

Corteza Cerebral , Dieta Alta en Grasa , Obesidad , Animales , Ratones , Femenino , Obesidad/genética , Obesidad/metabolismo , Masculino , Corteza Cerebral/metabolismo , Genotipo , Modelos Animales de Enfermedad , Apolipoproteína E4/genética , Apolipoproteína E3/genética , Factores Sexuales , Ratones Transgénicos , Apolipoproteínas E/genética , Humanos , Expresión Génica

RESUMEN

Apolipoprotein E (apoE) is a regulator of lipid metabolism, cholesterol transport, and the clearance and aggregation of amyloid ß in the brain. The three human apoE isoforms apoE2, apoE3, and apoE4 only differ in one or two residues. Nevertheless, the functions highly depend on the isoform types and lipidated states. Here, we generated novel anti-apoE monoclonal antibodies (mAbs) and obtained an apoE4-selective mAb whose epitope is within residues 110-117. ELISA and bio-layer interferometry measurements demonstrated that the dissociation constants of mAbs are within the nanomolar range. Using the generated antibodies, we successfully constructed sandwich ELISA systems, which can detect all apoE isoforms or selectively detect apoE4. These results suggest the usability of the generated anti-apoE mAbs for selective detection of apoE isoforms.

Asunto(s)

Anticuerpos Monoclonales , Apolipoproteínas E , Isoformas de Proteínas , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/química , Humanos , Isoformas de Proteínas/inmunología , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/química , Apolipoproteínas E/inmunología , Animales , Epítopos/inmunología , Epítopos/química , Ensayo de Inmunoadsorción Enzimática/métodos , Ratones , Apolipoproteína E4/genética , Apolipoproteína E4/inmunología , Apolipoproteína E4/metabolismo , Ratones Endogámicos BALB C , Apolipoproteína E3/inmunología , Apolipoproteína E3/genética , Apolipoproteína E3/química , Apolipoproteína E3/metabolismo

RESUMEN

OBJECTIVE: Dyslipidemia is a co-existing problem in patients with diabetes mellitus (DM) and coronary artery disease (CAD), and apolipoprotein E (APOE) plays an important role in lipid metabolism. However, the relationship between the APOE gene polymorphisms and the risk of developing CAD in type 2 DM (T2DM) patients remains controversial. The aim of this study was to assess this relationship and provide a reference for further risk assessment of CAD in T2DM patients. METHODS: The study included 378 patients with T2DM complicated with CAD (T2DM + CAD) and 431 patients with T2DM alone in the case group, and 351 individuals without DM and CAD were set as controls. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) - microarray. Differences in APOE genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for age, gender, body mass index (BMI), history of smoking, and history of drinking to access the relationship between APOE genotypes and T2DM + CAD risk. RESULTS: The frequencies of the APOE ɛ3/ɛ4 genotype and ε4 allele were higher in the T2DM + CAD patients, and the frequencies of the APOE ɛ3/ɛ3 genotype and ε3 allele were lower than those in the controls (all p < 0.05). The T2DM + CAD patients with ɛ4 allele had higher level in low-density lipoprotein cholesterol (LDL-C) than those in patients with ɛ2 and ɛ3 allele (p < 0.05). The results of logistic regression analysis showed that age ≥ 60 years old, and BMI ≥ 24.0 kg/m2 were independent risk factors for T2DM and T2DM + CAD, and APOE ɛ3/ɛ4 genotype (adjusted odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.18-3.14, p = 0.008) and ɛ4 allele (adjusted OR = 1.97, 95% CI = 1.23-3.17) were independent risk factors for T2DM + CAD. However, the APOE genotypes and alleles were not found to have relationship with the risk of T2DM. CONCLUSIONS: APOE ε3/ε4 genotype and ε4 allele were independent risk factors for T2DM complicated with CAD, but not for T2DM.

Asunto(s)

Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Humanos , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Apolipoproteínas E/genética , Genotipo , Factores de Riesgo , Apolipoproteína E3/genética , Alelos