Role Of apoE Research Articles

Abstract WP358: APOE Polymorphisms Influence Longitudinal Lipid Trends Preceding Primary Intracerebral Hemorrhage

Introduction: Primary intracerebral hemorrhage (ICH) remains one of the most severe forms of acute cerebrovascular disease. APOE ε2 and ε4 are risk factors for primary ICH, and also involved in regulation of circulating lipid levels. Hypercholesterolemia has been associated with reduced ICH risk. However, the biological mechanisms mediating the roles of APOE and serum lipids on ICH risk remain unclear. Given the pleiotropic relationship between APOE, ICH, and serum lipid levels, we sought to determine the influence of APOE genotype on temporal serum lipid trends before and after ICH. Methods: We performed a single-center retrospective longitudinal cohort analysis using subjects with known APOE genotype drawn from an ongoing cohort study of primary ICH. Serum lipid measurements for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) collected within 2 years preceding and following index ICH were extracted from electronic medical records (EMR). Piecewise linear mixed-effects random-coefficent models were used to compare APOE allele-specific effects on changes in serum lipid trends in ICH. Results: 124 ICH cases were analyzed. APOE ε4 carriers had significantly greater rates of decline in serum TC and LDL levels within 6 months prior to ICH (TC: -7.30 mg/dL/month, p=0.0035; LDL: -8.44 mg/dL/month, p=0.0001) compared to non-carriers (TC: -3.79 mg/dL/month, p=0.17; LDL: -2.39 mg/dL/month, p=0.55). In contrast, TC and LDL trends for APOE ε2 carriers were not significantly altered within the same time period. APOE genotype had no associations with serum HDL or TG trends. Conclusions: APOE allele status is a strong predictor of subacute serum TC and LDL changes preceding ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. While further studies are needed, our observation that APOE ε4 influences serum lipid trends preceding ICH provides additional insight towards lipid-dependent and lipid-independent APOE-genotype specific effects on stroke risk and suggests that characterization of the metabolic role of APOE is needed to improve understanding of APOE biology in cerebrovascular disease.

Aβ Metabolism and the Role of APOE in Alzheimer’s Disease

Disturbance of the production and clearance of Aβ in the brain is the main cause of memory and cognition decline and contributes strongly to the development of AD. In human, APOE gene has three isoforms, ε2, ε3 and ε4, with APOE ε4 as the most risk gene among them. In the development of AD pathophysiology, ApoE4 is positively associated with Aβ plague formation, but the mechanisms are not clear. In this review, we proposed a hypothesis that the effect of ApoE4 on Aβ possibly involves three processes: 1) ApoE4 can directly interact with Aβ and interferes Aβ clearance. 2) ApoE4 can compete with Aβ for the same receptor, that hinds the cellular uptake pathways of Aβ. 3) ApoE4 also modulates other Aβ degrading proteases like IDE to downregulate Aβ degradation, but the mechanisms needs to be further investigated. These findings suggest that the effect of ApoE in AD pathogenesis is complicated and modulation of ApoE is an attractive strategy for AD therapy.

APOE Stabilization by Exercise Prevents Aging Neurovascular Dysfunction and Complement Induction

Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's disease, but little is known about the processes that lead to age-related decline of brain structures and function. Here we use RNA-seq in combination with high resolution histological analyses to show that aging leads to a significant deterioration of neurovascular structures including basement membrane reduction, pericyte loss, and astrocyte dysfunction. Neurovascular decline was sufficient to cause vascular leakage and correlated strongly with an increase in neuroinflammation including up-regulation of complement component C1QA in microglia/monocytes. Importantly, long-term aerobic exercise from midlife to old age prevented this age-related neurovascular decline, reduced C1QA+ microglia/monocytes, and increased synaptic plasticity and overall behavioral capabilities of aged mice. Concomitant with age-related neurovascular decline and complement activation, astrocytic Apoe dramatically decreased in aged mice, a decrease that was prevented by exercise. Given the role of APOE in maintaining the neurovascular unit and as an anti-inflammatory molecule, this suggests a possible link between astrocytic Apoe, age-related neurovascular dysfunction and microglia/monocyte activation. To test this, Apoe-deficient mice were exercised from midlife to old age and in contrast to wild-type (Apoe-sufficient) mice, exercise had little to no effect on age-related neurovascular decline or microglia/monocyte activation in the absence of APOE. Collectively, our data shows that neurovascular structures decline with age, a process that we propose to be intimately linked to complement activation in microglia/monocytes. Exercise prevents these changes, but not in the absence of APOE, opening up new avenues for understanding the complex interactions between neurovascular and neuroinflammatory responses in aging and neurodegenerative diseases such as Alzheimer’s disease.

Production of Cloned Miniature Pigs Expressing High Levels of Human Apolipoprotein(a) in Plasma.

High lipoprotein(a) [Lp(a)] levels are a major risk factor for the development of atherosclerosis. However, because apolipoprotein(a) [apo(a)], the unique component of Lp(a), is found only in primates and humans, the study of human Lp(a) has been hampered due to the lack of appropriate animal models. Using somatic cell nuclear transfer (SCNT) techniques, we produced transgenic miniature pigs expressing human apo(a) in the plasma. First, we placed the hemagglutinin (HA)-tagged cDNA of human apo(a) under the control of the β-actin promoter and cytomegalovirus enhancer, and then introduced this construct into kidney epithelial cells. Immunostaining of cells with anti-HA antibody allowed identification of cells stably expressing apo(a); one of the positive clones was used to provide donor cells for SCNT, yielding blastocysts that expressed apo(a). Immunohistochemical analysis of tissue sections and RT-PCR analysis of total RNA from organs of cloned piglet revealed that apo(a) is expressed in various tissues/organs including heart, liver, kidney, and intestine. More importantly, a transgenic line exhibited a high level (>400 mg/dL) of Lp(a) in plasma, and the transgenic apo(a) gene was transmitted to the offspring. Thus, we generated a human apo(a)–transgenic miniature pig that can be used as a model system to study advanced atherosclerosis related to human disease. The anatomical and physiological similarities between the swine and human cardiovascular systems will make this pig model a valuable source of information on the role of apo(a) in the formation of atherosclerosis, as well as the mechanisms underlying vascular health and disease.

The role of ApoE-4 in hippocampal hyperactivity in amnestic mild cognitive impairment

The role of ApoE-4 in hippocampal hyperactivity in amnestic mild cognitive impairment

Association of Apolipoprotein E Alleles with Susceptibility to Age-Related Macular Degeneration in Iranian Patients

Background: This study aimed at investigating the association between alleles and genotypes of APOE and developing Age-related macular degeneration (AMD). Materials and Methods: After ophthalmological examination, 120 patients with confirmed AMD and 120 healthy controls were enrolled. The polymorphic segment of APOE gene was PCR-amplified and sequenced to determine the frequency distribution of polymorphic alleles and genotypes of this gene in sample population. Results: The frequency distribution of APOE alleles and genotypes differed significantly between the patients and control groups (P<0.05). The frequency of APOEe2 was higher in patients than that of the controls (P = 0.00) and this variant allele showed a significant association with AMD even after removal of the effects of age, sex and smoking in logistic regression analysis (P = 0.00, OR= 3.439; CI 95% 1.664-7.108). On the other hand, the frequency distribution of APOEe4 was not statistically different between patients and healthy controls. Conclusion: The results showed a moderate positive association between APOE e2 and AMD, but no specific role was found for APOE e4 in protection against AMD. However, more studies are required to clarify the possible role of APOE in the pathogenesis of AMD.

Genetic Risk Factors for Delirium. Meta-analysis of the Association of Apolipoprotein E Epsilon 4 Allele and Delirium

Introduction The role of APOE in Alzheimer’s disease and other dementias has been intensively investigated. However APOE in delirium has only recently been investigated in studies with small samples. There is evidence that APOE relates to delirium by one or more of the following pathophysiological mechanism: a) inhibition of inflammation in the CNS during acute illness, with release of inflammatory mediators, b) modification of inflammatory responses in an isoform-specific manner, c) by blocking both nicotine and acetylcholine receptors causing the anticholinergic effect which is assumed in delirium. Objectives A meta-analysis of the published pooled data seems timely to establish any relationship between APOE and delirium, and to determine further direction of research in this topic. Aims To find out if there is any direct relationship between the APOE epsilon 4 and the occurrence of delirium. Methods Pubmed, MEDLINE, EBSCOhost and Google Scholar have been searched with the relevant keywords, and from the references of relevant papers. Nine papers were found which examined the relationship between APOE and delirium. Data were extracted from 8 of them and were pooled for meta-analysis using random effects with R software. Results Data from 1762 participants showed no heterogeneity (Q=13.55, df:7, p=0.06). The possession of the APOE epsilon 4 allele has a small (OR:1.17, CI:0.77-1.80), non-significant (p=0.45) effect in the presence of delirium. Conclusions There is no association between APOE and the occurrence of delirium. Confirmation and clarification in larger studies could have important clinical implications for predicting prognosis and for treatment of delirium.

Role of ApoA1 on high-density lipoprotein: an intervention with plant sterols in patients with hypercholesterolemia.

Numerous studies have shown an inverse association between cholesterol´s concentration associated with High-Density Lipoprotein Cholesterol (HDL-C) and cardiovascular risk. The present study intends to investigate the possible relation between Apolipoprotein A (ApoA1) and HDL-C as a new strategy to reduce cardiovascular risk. was determine the effect of ApoA1 in cholesterol ´s metabolism through its influence on HDL-C in young adult population. One clinical trial, controlled, randomized, double-blind, providing a commercial milk, "Naturcol", with sterols for 3 weeks (n = 19) and placebo (n = 16). A questionnaire Ad Hoc was designed and a complete anthropometric study was made. SPSS 21.0 was used to analyse the data. Significant differences were observed between sterol milk and placebo in a single marker, Low-Density Lipoprotein Cholesterol (LDL-C). A linear dispersion of data between HDL-C and ApoA1 was found, both at the beginning and end of the intervention (Person Correlation = 0.846 and 0.903, respectively). High dependency measures by linear regression (R2= 0.715 and 0.816, respectively) were observed. A significant relation between HDL-C and ApoA1 was proven. Taking into account the importance that HDL-C levels seem to have on cardiovascular health, ApoA1 is presented as an important clinical marker to improve heart function as well as to reduce cardiovascular risk.

Abstract LB-3: Apolipoprotein (E) is a determinant of colon carcinogenesis potentially by regulating inflammation and β-catenin independently of its role in lipid metabolism

Abstract Colorectal cancer is a leading cause of cancer-related mortality. Apolipoprotein E (ApoE) is a major player in cholesterol metabolism and has been suggested, through association studies, to play a role in colon homoeostasis and cancer. Genetic studies suggested that polymorphisms in the ApoE alleles constitute a risk factor for the development of colon cancer. Collectively, these studies explored the role of ApoE in colon cancer by narrowly focusing on its established function in lipid metabolism. In the current study, we utilized a genetic mouse model (ApcMin mouse) of colon cancer to test the hypothesis that ApoE is a determinant in the disease progression. We show that ApoE gene heterozygosity, which reduces the protein (∼50%) and minimally affects the lipid profile, significantly increased tumor burden in ApcMin mice both in the small intestine and the colon. Surprisingly, ApoE gene knockout, which completely eliminates the protein and drastically elevates the lipid profile, did not aggravate the tumor burden in ApcMin mice compared to that caused by gene heterozygosity, suggesting a novel and cholesterol-metabolism-independent function for ApoE in colon homeostasis. In vitro studies with primary colon epithelial cells, isolated using a novel technique developed by our laboratory, show that ApoE-deficiency achieved by ApoE heterozygosity, knockout, or knockdown increased the level of active β-catenin in the absence of any stimulation. It appears that such increase in β-catenin may be at an mRNA level. ApoE deficiency was also associated with an increase in inflammatory factors including VCAM-1, MCP-1, and COX-2 in TNF-treated colon epithelial cells. Altogether, our preliminary results suggest a major role of ApoE in colon homeostasis and that deficiency in ApoE levels may constitute a risk factor for colon cancer progression. Citation Format: Ali I. Elbahrawy, Abdelmetalab Tarhuni, Amarjit S. Naura, Youssef Errami, Mohamed Alwan, Samar Hammad, Jimena Trillo-Tinoco, Ramadan Hemeida, Hassan Brim, Hassan Ashktorab, Luis Del Valle, Hamid A. Boulares. Apolipoprotein (E) is a determinant of colon carcinogenesis potentially by regulating inflammation and β-catenin independently of its role in lipid metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-3. doi:10.1158/1538-7445.AM2014-LB-3

Apolipoprotein A1 Regulates Coenzyme Q10 Absorption, Mitochondrial Function, and Infarct Size in a Mouse Model of Myocardial Infarction

HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1null (apoA1−/−) and apoA1heterozygous (apoA1+/−) mice. We observed that apoA1+/− and apoA1−/− mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia–reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1−/− mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation.

Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4

The apolipoprotein (apo) E4 isoform has consistently emerged as a susceptibility factor for late-onset Alzheimer disease (AD), although the exact mechanism is not clear. A rare apoE4 mutant, apoE4[L28P] Pittsburgh, burdens carriers with an added risk for late-onset AD and may be a useful tool for gaining insights into the role of apoE4 in disease pathogenesis. Toward this end, we evaluated the effect of the L28P mutation on the structural and functional properties of apoE4. ApoE4[L28P] was found to have significantly perturbed thermodynamic properties, to have reduced helical content, and to expose a larger portion of the hydrophobic surface to the solvent. Furthermore, this mutant is thermodynamically destabilized and more prone to proteolysis. When interacting with lipids, apoE4[L28P] formed populations of lipoprotein particles with structural defects. The structural perturbations brought about by the mutation were accompanied by aberrant functions associated with the pathogenesis of AD. Specifically, apoE4[L28P] promoted the cellular uptake of extracellular amyloid β peptide 42 (Aβ42) by human neuroblastoma SK-N-SH cells as well as by primary mouse neuronal cells and led to increased formation of intracellular reactive oxygen species that persisted for at least 24 h. Furthermore, lipoprotein particles containing apoE4[L28P] induced intracellular reactive oxygen species formation and reduced SK-N-SH cell viability. Overall, our findings suggest that the L28P mutation leads to significant structural and conformational perturbations in apoE4 and can induce functional defects associated with neuronal Aβ42 accumulation and oxidative stress. We propose that these structural and functional changes underlie the observed added risk for AD development in carriers of apoE4[L28P].

67 Perturbing NMDA Receptor -PSD-95 Protein Interactions Prevents Selective Loss of Nitric Oxide Synthase (NOS) Containing Neuron and Improves Gastric Emptying in Diabetic Rats

Background. Although the pathogenesis of delayed gastric emptying, namely gastroparesis, is still unclear, diabetes mellitus is major etiology of gastroparesis. Decreased neuronal nitric oxide synthase (nNOS), which induces relaxation of gastric smooth muscle through the production of nitric oxide, is supposed to be one of the mechanisms of gastroparesis (Gastroenterology 113:1535, 1997). However, the effective treatment for gastroparesis has not been developed. While dyslipidemia is a risk factor of diabetic neuropathy, the defect of apolipoprotein E (apoE), a lipid transporter secreted from glial cell, decreased the expression of nNOS in the stomach (Dig Dis Sci. 57:1504, 2012). Furthermore, transplantion of neural stem cell into gastric antral wall was reported to improve delayed gastric emptying in nNOS knockout mouse (Gastroenterology 129:1817, 2005). The aim of the present study is to explore the role of apoE on gastric emptying and evaluate the effect of neural stem cell transplantation against the model of gastroparesis. Methods. The model of type2 diabetes, db/db mice, and apoE knockout mice, which is the model of arteriosclerosis and hyperlipidemia, were used. For measurement of gastric emptying, 0.48 mg of 13C-acetic acid with 0.15 ml liquid meal (Lacol®) was orally administered. The gastric half emptying time (t1/2) measured by 13C breath test was used for evaluation. The expression levels of nNOS, pan-neuronal marker, PGP 9.5, glial fibrillary acidic protein (GFAP), and glia derived neurotrophic factor (GDNF) were examined by immunohistochemistry andWestern blotting. Neural stem cells were isolated from ffLuc-transgenic mouse, which fluorescent protein, venus, and luciferase gene was fused (BBRC 419; 188, 2012). After tertiary neurosphere was formed, it was injected into gastric antral wall by glass needle. Results. Delayed gastric emptying was observed in 27% of db/db mice, while the levels of blood glucose and body weight were not significantly different. The expression of nNOS in gastric antrum and serum level of apoE were significantly decreased in db/db mice which presented delayed gastric emptying. In apoE knockout mice, the gastric emptying was also delayed compared with control. Although, the expression of PGP 9.5 was not changed, the expression of nNOS was significantly decreased in apoE knockout mice. Furthermore, the expression levels of GFAP and GDNF were significantly decreased in apoE knockout mice. Transplantation of neural stem cell significantly improved the delayed gastric emptying in apoE knockout mice. Conclusion. Neural stem cell transplantation restored the delayed gastric emptying in apoE knockout mice, suggesting a promising application of regenerative therapy against gastroparesis.

66 Neural Stem Cell Transplantation Restored the Delayed Gastric Emptying in Apolipoprotein E-Knockout Mice

Background. Although the pathogenesis of delayed gastric emptying, namely gastroparesis, is still unclear, diabetes mellitus is major etiology of gastroparesis. Decreased neuronal nitric oxide synthase (nNOS), which induces relaxation of gastric smooth muscle through the production of nitric oxide, is supposed to be one of the mechanisms of gastroparesis (Gastroenterology 113:1535, 1997). However, the effective treatment for gastroparesis has not been developed. While dyslipidemia is a risk factor of diabetic neuropathy, the defect of apolipoprotein E (apoE), a lipid transporter secreted from glial cell, decreased the expression of nNOS in the stomach (Dig Dis Sci. 57:1504, 2012). Furthermore, transplantion of neural stem cell into gastric antral wall was reported to improve delayed gastric emptying in nNOS knockout mouse (Gastroenterology 129:1817, 2005). The aim of the present study is to explore the role of apoE on gastric emptying and evaluate the effect of neural stem cell transplantation against the model of gastroparesis. Methods. The model of type2 diabetes, db/db mice, and apoE knockout mice, which is the model of arteriosclerosis and hyperlipidemia, were used. For measurement of gastric emptying, 0.48 mg of 13C-acetic acid with 0.15 ml liquid meal (Lacol®) was orally administered. The gastric half emptying time (t1/2) measured by 13C breath test was used for evaluation. The expression levels of nNOS, pan-neuronal marker, PGP 9.5, glial fibrillary acidic protein (GFAP), and glia derived neurotrophic factor (GDNF) were examined by immunohistochemistry andWestern blotting. Neural stem cells were isolated from ffLuc-transgenic mouse, which fluorescent protein, venus, and luciferase gene was fused (BBRC 419; 188, 2012). After tertiary neurosphere was formed, it was injected into gastric antral wall by glass needle. Results. Delayed gastric emptying was observed in 27% of db/db mice, while the levels of blood glucose and body weight were not significantly different. The expression of nNOS in gastric antrum and serum level of apoE were significantly decreased in db/db mice which presented delayed gastric emptying. In apoE knockout mice, the gastric emptying was also delayed compared with control. Although, the expression of PGP 9.5 was not changed, the expression of nNOS was significantly decreased in apoE knockout mice. Furthermore, the expression levels of GFAP and GDNF were significantly decreased in apoE knockout mice. Transplantation of neural stem cell significantly improved the delayed gastric emptying in apoE knockout mice. Conclusion. Neural stem cell transplantation restored the delayed gastric emptying in apoE knockout mice, suggesting a promising application of regenerative therapy against gastroparesis.

Strain differences in the expression of cholinergic markers in the hippocampus of ApoE-knockout and C57BL/6J mice

Our recent study suggests that mice deficient in ApoE may exhibit impaired learning and memory. Here we designed the present study to investigate the association between ApoE deficiency and cholinergic markers expression in the hippocampus of ApoE-knockout (ApoE-KO) and wild-type (WT) mice. Hippocampal slices were collected and the mRNA levels of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) and the protein level of ChAT were analyzed. We show that ApoE-KO exhibited a distinctly lower ChAT mRNA and protein levels in the hippocampus compared with WT mice. There were no strain effects on AChE mRNA. Our data provide evidence supporting the role of ApoE in the expression of ChAT, which may suggest a possible link between cholinergic deficit and poorer performance in ApoE-KO mice.

Association betweenε2/3/4, Promoter Polymorphism (−491A/T, −427T/C, and −219T/G) at the Apolipoprotein E Gene, and Mental Retardation in Children from an Iodine Deficiency Area, China

Background. Several common single-nucleotide polymorphisms (SNPs) at apolipoprotein E (ApoE) have been linked with late onset sporadic Alzheimer's disease and declining normative cognitive ability in elder people, but we are unclear about their relationship with cognition in children. Results. We studied −491A/T, −427T/C, and −219G/T promoter polymorphisms and ε2/ε3/ε4 at ApoE among children with mental retardation (MR, n = 130), borderline MR (n = 124), and controls (n = 334) from an iodine deficiency area in China. The allelic and genotypic distribution of individual locus did not significantly differ among three groups with Mantel-Haenszel χ 2 test (P > 0.05). However, frequencies of haplotype of −491A/−427T/−219T/ε4 were distributed as MR > borderline MR > controls (P uncorrected = 0.004), indicating that the presence of this haplotype may increase the risk of disease. Conclusions. In this large population-based study in children, we did not find any significant association between single locus of the four common ApoE polymorphisms (−491A/T, −427T/C, −219T/G, and ε2/3/4) and MR or borderline MR. However, we found that the presence of ATTε4 haplotype was associated with an increased risk of MR and borderline MR. Our present work may help enlarge our knowledge of the cognitive role of ApoE across the lifespan and the mechanisms of human cognition.

The influence of apoE-deficiency and LDL-receptor-deficiency on the HDL subpopulation profile in mice and in humans

ObjectiveAs apoE−/− and LDL-Receptor−/− mice are commonly used in atherosclerosis research; our objective was to point out the differences in HDL metabolism between mice and humans regarding the roles of apoE and LDLR. MethodsWe examined HDL particles obtained from wild type (WT), LDLR−/−, and apoE−/− mice, as well as from normal, homozygous familial hypercholesterolemic (FH), and apoE-deficient human subjects by 2-dimensional non-denaturing PAGE followed by immunoblot and image analysis. ResultsIn WT mice, the majority of apoA-I was in large (9.0–12.0 nm), α-mobility HDL with trace amounts of apoA-I in small, preβ-1 HDL. In LDL−/− mice, both apoA-I- and apoE-containing HDL looked normal. About one-third of apoE was associated with large apoA-I-containing HDL (LpA-I:E) and two-thirds formed large HDL without apoA-I (LpE). In apoE−/− mice, apoA-I was detected in multiple, β-preβ-mobility, tightly-packed bands (7.0–13.0 nm) indicating that apoA-I in these animals was present only in poorly-lipidated, discoidal particles. Neither FH nor apoE-deficient humans showed significant alterations in apoA-I-containing HDL particles as compared to non-carriers. ConclusionsOur data indicate that apoE is necessary for the formation of spherical, lipidated HDL particles in mice, but not in humans, probably because mice lack CETP. Based on our data, we hypothesize that apoE−/− mice have little or no functional HDL, therefore results from apoE−/− mice cannot be extrapolated to humans without taking this significant difference into consideration.

Lipoprotein glomerulopathy in China

Lipoprotein glomerulopathy (LPG), a rare renal disease, is mainly reported in Japan and China. Chinese cases of LPG showed similar clinical and pathological features as reports from other countries. Three types of APOE mutation have been detected in those patients: APOE Maebashi (142Arg-144Leu-0) and APOE Kyoto (Arg25-Cys) were initially reported, and APOE Guangzhou (Arg150-Pro) is a novel mutation in Chinese patients with LPG. Asymptomatic carriers of all three mutations exist in families, but serum lipid and apolipoprotein E (apoE) levels are markedly elevated. In most of Chinese patients with LPG, long-term treatment with statins or bezafibrates appears to decrease proteinuria. LPG provides a disease model by which to explore pathogenic roles of apoE in common diseases.

Vascular hypothesis of Alzheimer’s disease: role of apoE and apoE receptors

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease that has emerged as the most prevalent form of late-life dementia in humans [1]. Production of amyloid-b (Ab) from the amyloid precursor protein (APP) and its subsequent accumulation, aggregation and deposition in the brain are central events in the pathogenesis of AD [1]. Cerebral amyloid angiopathy (CAA) is a major pathological feature of AD where amyloid spreads and deposits throughout the blood vessel walls in the central nervous system. These pathogenic events induce a specific clinical presentation profile including cerebral hemorrhage, stroke, ischemic infarctions, subarachnoid hemorrhage, seizures, cognitive impairment and dementia [2]. While Ab is a key molecule in AD, epidemiological studies have shown that several well-established risk factors for AD, including diabetes mellitus, atherosclerosis, stroke, hypertension, transient ischemic attacks, microvessel pathology and smoking, have a vascular component that reduces cerebral perfusion [3]. In fact, detection of regional cerebral hypoperfusion through neuroimaging techniques can preclinically identify individuals at risk for AD. Further, cerebral hypoperfusion precedes hypometabolism, cognitive decline, and neurodegeneration in AD [3]. Therefore, disturbance of cerebrovascular system is likely a major contributor to AD pathogenesis. Among the three human apolipoprotein E (apoE) isoforms (E2, E3 and E4), APOE4 is the strongest genetic risk factor for late-onset AD. The most consistent finding that differentiates apoE4 from apoE3 is their respective roles in brain Ab clearance, where apoE4 is less efficient than apoE3 in promoting Ab clearance [4]. In addition, APOE4 also increases the risk for CAA and vascular dementia [4]. Because apoE4 is known to damage blood-brain barrier (BBB) integrity and reduces small cerebral vessels [5], apoE is likely involved in the maintenance of cognitive function through regulating the function of cerebrovascular systems.

Apolipoprotein A1 potentiates lipoxin A4 synthesis and recovery of allergen‐induced disrupted tight junctions in the airway epithelium

Asthma is characterized by chronic airway inflammation triggered by various allergens in the environment. Defects in the bronchial epithelial interface with the external environment are the hallmark of asthma. Apolipoprotein A-1 (ApoA1) or ApoA1 mimetics have demonstrated anti-inflammatory activity and preventive effects in mouse models. We investigated airway levels of ApoA1 in asthmatics and the possible role of ApoA1 in protection of the bronchial epithelium and in resolution of inflammation in cellular and animal models of asthma. ApoA1 levels were measured in bronchoalveolar lavage fluid (BALF) from asthmatics and healthy controls. With treatment of ApoA1, mouse model of house dust mite (HDM)-driven asthma and cultured primary bronchial epithelial cells obtained from asthmatics were examined. Tight junction (TJ) expression in the bronchial epithelial cells was assessed by using confocal microscopy and immunoblot. Asthmatics showed significantly lower ApoA1 levels in bronchoalveolar lavage fluid than did healthy controls. Local ApoA1 treatment significantly decreased lung IL-25, IL-33, and thymic stromal lymphopoietin levels in HDM-challenged mice and inhibited allergen-induced production of these cytokines in cultured primary bronchial epithelial cells. ApoA1 promoted recovery of disrupted TJ proteins zonula occludens-1 and occludin in cultured primary bronchial epithelium obtained from asthmatics. ApoA1-induced increases in the TJ proteins were dependent on increased production of lipoxin A4 (LX A4). ApoA1 enhances resolution of allergen-induced airway inflammation through promoting recovery of damaged TJs in the bronchial epithelium. ApoA1 could be a therapeutic strategy in chronic airway inflammatory diseases that are associated with a defective epithelial barrier, including asthma.

Role of ApoE and its isoforms in AMD

Role of ApoE and its isoforms in AMD