Apolipoprotein E2 inhibits mitochondrial apoptosis in pancreatic cancer cells through ERK1/2/CREB/BCL-2 signaling.

BACKGROUND: Apolipoprotein E2 (ApoE2) is a pleiotropic protein that influences several aspects of cancer metabolism and development. Evading apoptosis is a vital factor for facilitating cancer cell growth. However, the role and mechanism of ApoE2 in regulating cell apoptosis of pancreatic cancer remain unclear. METHODS: In this study, we firstly detected the mRNA and protein expressions of ApoE2 in PANC-1 and Capan-2 cells by real-time polymerase chain reaction and Western blotting. We then performed TUNEL and flow cytometric analyses to explore the role of recombinant human ApoE2, pCMV6-ApoE2 and siApoE2 in the apoptosis of PANC-1 and Capan-2 cells. Furthermore, we investigated the molecular mechanism through which ApoE2 affected apoptosis in PANC-1 cells using immunofluorescence, immunoprecipitation, Western blotting and co-immunoprecipitation analysis. RESULTS: ApoE2 phosphorylated ERK1/2 and inhibited pancreatic cancer cell apoptosis. In addition, our data showed that ApoE2/ERK1/2 altered the expression and mitochondrial localization of BCL-2 via activating CREB. ApoE2/ERK1/2/CREB also increased the total BCL-2/BAX ratio, inhibited the opening of the mitochondrial permeability transition pore and the depolarization of mitochondrial transmembrane potential, blocked the leakage of cytochrome-c and the formation of the apoptosome, and consequently, suppressed mitochondrial apoptosis. CONCLUSIONS: ApoE2 regulates the mitochondrial localization and expression of BCL-2 through the activation of the ERK1/2/CREB signaling cascade to evade the mitochondrial apoptosis of pancreatic cancer cells. ApoE2 may be a distinct prognostic marker and a potential therapeutic target for pancreatic cancer.

Apolipoprotein E-related glomerular disorders.

Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been characterized. ApoE2 homozygote glomerulopathy has been found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages, and occasionally with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, in which non-immune membranous nephropathy-like features were observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells. Recent studies have suggested that LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure, and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may contribute to the accumulation of lipoproteins in the glomerulus, causing lipoprotein thrombi in LPG.

Apolipoprotein E2 modulates cell cycle function to promote proliferation in pancreatic cancer cells via regulation of the c-Myc-p21Waf1 signalling pathway.

Apolipoprotein E2 (ApoE2) is reportedly critical for cell proliferation and survival, and has been identified as a potential tumour-associated marker in many kinds of cancer. However, studies of the function and mechanisms of ApoE2 in pancreatic cancer proliferation and development are rare. In this study, we performed an analysis to determine the modulatory effects of ApoE2-LRP8 (lipoprotein receptor-related protein 8) pathway on cell cycle and cell proliferation, and explored its mechanisms in pancreatic cancer. High expression levels of ApoE2-LRP8/c-Myc were detected in tumour tissues and cell lines by immunohistochemistry and Western blotting. It was also shown that ApoE2-LRP8 induced phosphorylation of ERK1/2 to activate c-Myc and contribute to cell-cycle-related protein expression. ApoE2 conditions induced c-Myc binding to target gene sequences in the p21Waf1 promoter, resulting in decreased transcription. ERK/c-Myc contributes to the promotion of the expression levels of cyclin D1, cdc2, and cyclin B1, and reduces p21Waf1 activity, thereby promoting cell cycle distribution. We demonstrated the function of ApoE2-LRP8 in the activation of the ERK-c-Myc-p21Waf1 signalling cascade and the modulation of G1/S and G2/M transition, indicating ApoE2-LRP8's important role in the cancer cell proliferation. ApoE2 could serve as a diagnostic marker and chemotherapeutic target in pancreatic cancer.

Is Apolipoprotein E ε2 Associated with Delayed Onset of Non-Lesional Temporal Lobe Epilepsy?

The aim of the study was to evaluate the possible association between Apo E polymorphisms and age at seizure onset in patients with non-lesional temporal lobe epilepsy. Eighty patients with non-lesional temporal lobe epilepsy with or without bilateral tonic-clonic propagation were analyzed. Age at seizure onset was defined as age at the first unequivocal seizure (excluding febrile convulsions). ApoE alleles were determined by a procedure where genome DNA was amplified by chain reaction along with polymerase, using the LightCycler kit (Roche) for ApoE mutations on codons 112 and 158. There was a statistically significant difference between the groups of patients with ApoE ε2/3 and ε3/4 genotypes (p=0.03), but not between patients with ApoE, ε2/3 and ε3/3, and those with ApoE ε3/4 and ε3/3. In conclusion, the results of our study suggested positive association of a specific ApoE genotype and onset of non-lesional temporal lobe epilepsy.

Genomic structure and genetic drift in C57BL/6 congenic metabolic mutant mice.

We used a genome-wide single nucleotide polymorphism (SNP) approach to characterize the genomic structures of four representative C57BL/6 (B6) congenic mutant mouse lines to include the A) long-chain acyl-CoA dehydrogenase (Acadl), B) melanocortin 3 receptor (Mc3r), C) endothelial nitric oxide synthase (Nos3), and D) a replacement of mouse apolipoprotein E (Apoe) by human apolipoprotein E-2 (APOE2). We wanted to evaluate the size and flanking genes of the 129 strain origin mutant allele intervals on the B6 background. Additionally, we wanted to evaluate genetic drift among not only the four mutant lines and their respective B6 origin substrains, but also the drift between two commonly used B6 lines obtained from Jackson Laboratory and Taconic. Overall, we found a range of 129 origin interval sizes in the congenic mutant lines analyzed that ranged from a ~2.8 kb human sequence for APOE2 embedded in a 129S6 interval to the largest being a ~16 Mb fragment containing the targeted Nos3 (eNos) gene. Given the range of 129 strain interval sizes, we found 129 strain flanking genes via annotation in genome data bases ranging from one gene both upstream and downstream of the APOE2 allele to seven genes-upstream and five genes-downstream at the Nos3 locus. Furthermore, we found fourteen SNP differences between the Jackson Laboratory and Taconic B6 mice. These genetic differences were associated with marked adiposity differences between the two B6 substrains. This study demonstrates both the fidelity and the caveats of using congenic gene targeted mouse models and recognizing the importance of selecting the appropriately matched wild-type control mouse line.

Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits.

Recently, several cases of novel apolipoprotein E (apoE)-related glomerular disease known as membranous nephropathy (MN)-like apoE deposition disease with apoE Toyonaka (Ser197Cys) and homozygous apoE2/2 have been reported. However, the clinical and pathological characteristics are uncertain due to the small number of reports. Here, we report an additional case with various clinical and pathological characteristics. A 28-year-old Japanese man with mild proteinuria and hematuria underwent a kidney biopsy. Examination under a light microscope revealed mesangial proliferation, mesangial matrix expansion, and segmental spike lesion. An immunofluorescence study showed no immunoglobulin or complement depositions. In the electron microscopic (EM) examination, massive deposits with various electron densities in the subepithelial, subendothelial, and paramesangial areas were more prominent than those reported in previous cases, which resembled microbubbles or microcysts on higher magnification. The glomerular basement membrane (GBM) structure was partly degenerated by these deposits. Serum triglyceride and cholesterol levels were within the normal range. However, the serum apoE concentration was significantly high, and glomerular apoE accumulation was detected in immunohistochemistry. The DNA sequence revealed apoE Toyonaka and homozygous apoE2/2 similar to that of the previous cases with MN-like apoE deposition disease. MN-like apoE deposition disease can manifest as only mild hematuria and proteinuria without dyslipidemia. Various characteristic deposits associated with GBM degeneration can be observed in the EM study.

Apolipoprotein E2 Promotes the Migration and Invasion of Pancreatic Cancer Cells via Activation of the ERK1/2 Signaling Pathway.

BACKGROUND: Apolipoprotein E2 (ApoE2) is reported to be essential for cell metastasis and proliferation and has been considered a potential diagnostic marker in many cancers. However, the function of ApoE2 in the metastasis of pancreatic cancer, as well as the underlying mechanism, remain unclear. PURPOSE: In this study, we explored the effect of ApoE2 on the migration and invasion abilities of pancreatic cancer cells and explored the underlying molecular mechanism. METHODS AND RESULTS: Wound healing and Matrigel Transwell assays were used to investigate the role of ApoE2 in cell migration and invasion. Western blotting analysis showed that ApoE2 was overexpressed in pancreatic cancer tissues. Additionally, the overexpression of ApoE2 promoted the process of epithelial-mesenchymal transition (EMT) and enhanced the expression of MMP-2/9 in pancreatic cancer cells. Mechanistically, we found that inhibition of ERK1/2 signaling with PD98059 impaired the ApoE2-mediated promotion of cell migration, invasion and EMT. CONCLUSION: This study demonstrated that ApoE2/ERK1/2 signaling promoted the migration and invasion of pancreatic cancer cells. ApoE2 might be a potential therapeutic target for the treatment of pancreatic cancer metastasis.

Isoform and tissue dependent impact of apolipoprotein E on adipose tissue metabolic activation: The role of apolipoprotein A1.

Adipose organ is made of white (WAT) and brown (BAT) adipose tissue which are primarily responsible for lipid storage and energy production (heat and ATP) respectively. Metabolic activation of WAT may ascribe to this tissue characteristics of BAT, namely non-shivering thermogenesis and ATP production. Recent data indicate that apolipoproteins E (APOE) and A1 (APOA1) regulate WAT mitochondrial metabolic activation. Here, we investigated the functional cross-talk between natural human APOE2 and APOE4 isoforms with APOA1 in this process, using Apoe2knock-in and Apoe4knock-in mice. At baseline when Apoe2knock-in and Apoe4knock-in mice express both APOE and Apoa1, the Apoe2knock-in strain appears to have higher mitochondrial oxidative phosphorylation levels and non-shivering thermogenesis in WAT compared to Apoe4knock-in mice. When mice were switched to a high-fat diet for 18 weeks, circulating levels of endogenous Apoa1 in Apoe2knock-in mice became barely detectable though significant levels of APOE2 were still present. This change was accompanied by a significant reduction in WAT mitochondrial Ucp1 expression while BAT Ucp1 was unaffected. Ectopic APOA1 expression in Apoe2knock-in animals potently stimulated WAT but not BAT mitochondrial Ucp1 expression providing further evidence that APOA1 potently stimulates WAT non-shivering thermogenesis in the presence of APOE2. Ectopic expression of APOA1 in Apoe4knock-in mice stimulated BAT but no WAT mitochondrial Ucp1 levels, suggesting that in the presence of APOE4, APOA1 is a trigger of BAT non-shivering thermogenesis. Overall, our data identified a tissue-specific role of the natural human APOE2 and APOE4 isoforms in WAT- and BAT-metabolic activation respectively, that appears dependent on circulating APOA1 levels.

APOE2: protective mechanism and therapeutic implications for Alzheimer's disease.

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer's disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-ß (Aß)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.

A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes.

A 47-year-old Japanese man with mild proteinuria was treated with an ACE inhibitor and antiplatelet agent for 7 years. However, urinary protein levels increased and renal biopsy was performed. Eight out of 20 glomeruli showed global or segmental sclerosis with foamy changes or bubbles, but with a different appearance to typical foam cells or lipoprotein thrombi. "Spike" formation, as observed in membranous nephropathy (MN), was segmentally detected in methenamine silver-stained sections. In an immunofluorescence study, weak linear patterns for IgG and scanty deposits for C3 were observed in glomeruli, but were not specific for immunogenetic MN. An electron microscopy study showed highly dense deposits in the subepithelial, subendothelial, and mesangial areas, in which microbubbles appeared under a higher magnification. Since this case exhibited hypertriglyceridemia and cholesterolemia with high serum apolipoprotein E (apoE) clinically and homozygous apoE2/2 by apoE phenotype and genotype analyses, apoE2 homozygote glomerulopathy was diagnosed and various lipid-lowering agents, e.g., probucol, fenofibrate, and ezetimibe, were administered. However, renal dysfunction gradually developed and peritoneal dialysis was initiated 11 years after the diagnosis. ApoE Toyonaka (Ser197Cys) and homozygous E2/2 were recently identified by direct DNA sequencing. Therefore, non-immune MN-like lesions may develop with the combination of these apoE mutations.

Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2.

A 20-year-old female student underwent renal biopsy because of chance proteinuria and hematuria. Histological study revealed a membranous nephropathy-like appearance by light microscopy. But immunoglobulins and complements were negative in the glomerulus by immunofluorescence study. On the other hand, plasma apolipoprotein E (ApoE) concentration was elevated to more than 2 times the normal range, and the phenotype, genotype, and DNA sequence studies of her ApoE showed homozygous ApoE2/2 and a heterozygous novel missense mutation called ApoE Toyonaka (Ser197Cys). Detailed immunohistochemical studies found that the dense deposits in subepithelial, subendothelial, and mesangial areas contained ApoE. Tandem mass spectrometry also proved a large amount of ApoE in the glomerulus. These findings suggest that ApoE Toyonaka with a homozygous ApoE2/2 may cause a new form of ApoE-related glomerular disease resembling membranous nephropathy.

A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka.

A 79-year-old man was admitted to our hospital for proteinuria due to nephrotic syndrome. Renal biopsy revealed focal sclerosis and foam cell infiltration in the glomerulus. In addition, electron microscopic findings (EM) revealed peculiar electron-dense deposits (EDDs) in both sides of the glomerular basement membrane. Although subepithelial deposits had spike formation highly resembling those seen in membranous nephropathy (MN), immunoglobulins and complements were not identified by immunofluorescence study, and microbubbles appeared in high magnification of EM different from the immune disease. The analysis of apolipoprotein (Apo) E showed an elevated concentration of plasma ApoE. The phenotype, genotype, and DNA sequence studies revealed homozygous ApoE2/2 and a novel missense mutation called ApoE Toyonaka (Ser197Cys). This case may confirm the independent responsibility of ApoE2/2 and ApoE Toyonaka for ApoE2 homozygote glomerulopathy and MN-like EDD findings, respectively.

The Role of Alzheimer's and Cerebrovascular Pathology in Mediating the Effects of Age, Race, and Apolipoprotein E Genotype on Dementia Severity in Pathologically-Confirmed Alzheimer's Disease.

BACKGROUND: Dementia severity can be modeled as the construct δ, representing the "cognitive correlates of functional status." OBJECTIVE: We recently validated a model for estimating δ in the National Alzheimer's Coordinating Center's Uniform Data Set; however, the association of δ with neuropathology remains untested. METHODS: We used data from 727 decedents evaluated at Alzheimer's Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants' last visit prior to death were used to estimate dementia severity (δ). RESULTS: A structural equation model using age, education, race, and apolipoprotein E (APOE) genotype (number of ɛ2 and ɛ4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD. CONCLUSIONS: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity.

Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.

The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-ß (Aß) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aß levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aß burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aß and amyloid deposition. We further demonstrate that a widespread reduction of brain Aß burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.

Exploring the effect of the apolipoprotein E (APOE) gene on executive function, working memory, and processing speed during the early recovery period following traumatic brain injury.

INTRODUCTION: There is evidence that the e4 allele of the apolipoprotein E (APOE) gene is detrimental to cognitive function, but results from traumatic brain injury (TBI) populations are mixed. A possible explanation is that APOEe2 carriers have routinely been incorporated into APOEe4 and non-e4 groups, despite APOEe2 being proposed to have an ameliorative effect. Our primary aim was to investigate the influence of APOEe4 on cognitive impairment during early recovery following TBI, excluding the potential confound of APOEe2 possession. A secondary objective was to explore whether APOEe4 displays more pronounced effects in moderate to severe TBI and to consider the potential postinjury protective influence of the APOEe2 allele. METHOD: Participants who recently sustained a TBI (posttraumatic amnesia > 5 minutes) were assessed on measures of information processing speed, executive function, and working memory upon remission of posttraumatic amnesia. APOE genotype was determined by buccal saliva DNA extraction (APOEe4 n = 37, APOEe3 n = 92, APOEe2 n = 13). RESULTS: Stepwise multiple regressions were performed to compare APOEe4 carriers to APOEe3 homozygotes, with injury severity, age, and estimated premorbid IQ included in the first step. This model was found to significantly predict performance on all tasks, accounting for 17.3-24.3% of the variance. When APOEe4 status was added for the second step, there were no significant changes on any tasks (additional variance <1%). The effect of APOEe4 in moderate to severe TBI and the effect of APOEe2 were explored by analysis of covariance (ANCOVA), with no significant effects revealed. CONCLUSIONS: It is unlikely that APOE genotype influences cognitive function in the initial recovery period following TBI, regardless of injury severity. However, a more nuanced and long-term exploration of the effect of APOE genotype in the TBI population is warranted.

Human ApoE Isoforms Differentially Modulate Glucose and Amyloid Metabolic Pathways in Female Brain: Evidence of the Mechanism of Neuroprotection by ApoE2 and Implications for Alzheimer's Disease Prevention and Early Intervention.

Three major genetic isoforms of apolipoprotein E (ApoE), ApoE2, ApoE3, and ApoE4, exist in humans and lead to differences in susceptibility to Alzheimer's disease (AD). This study investigated the impact of human ApoE isoforms on brain metabolic pathways involved in glucose utilization and amyloid-ß (Aß) degradation, two major areas that are significantly perturbed in preclinical AD. Hippocampal RNA samples from middle-aged female mice with targeted human ApoE2, ApoE3, and ApoE4 gene replacement were comparatively analyzed with a qRT-PCR custom array for the expression of 85 genes involved in insulin/insulin-like growth factor (Igf) signaling. Consistent with its protective role against AD, ApoE2 brain exhibited the most metabolically robust profile among the three ApoE genotypes. When compared to ApoE2 brain, both ApoE3 and ApoE4 brains exhibited markedly reduced levels of Igf1, insulin receptor substrates (Irs), and facilitated glucose transporter 4 (Glut4), indicating reduced glucose uptake. Additionally, ApoE4 brain exhibited significantly decreased Pparg and insulin-degrading enzyme (Ide), indicating further compromised glucose metabolism and Aß dysregulation associated with ApoE4. Protein analysis showed significantly decreased Igf1, Irs, and Glut4 in ApoE3 brain, and Igf1, Irs, Glut4, Pparg, and Ide in ApoE4 brain compared to ApoE2 brain. These data provide the first documented evidence that human ApoE isoforms differentially affect brain insulin/Igf signaling and downstream glucose and amyloid metabolic pathways, illustrating a potential mechanism for their differential risk in AD. A therapeutic strategy that enhances brain insulin/Igf1 signaling activity to a more robust ApoE2-like phenotype favoring both energy production and amyloid homeostasis holds promise for AD prevention and early intervention.

Impact of the apolipoprotein E polymorphism, age and sex on neurogenesis in mice: pathophysiological relevance for Alzheimer's disease?

Apolipoprotein E (ApoE) is found in three different forms in humans (ApoE2, ApoE3 and ApoE4), and ApoE polymorphism is recognized as a major risk factor for Alzheimer's disease (AD). ApoE is involved in lipid and cholesterol transport, cell repair, and amyloid-ß deposition and certain studies suggest potential implications in neurogenesis. In this regard, we investigated the possible impact of the three different human ApoE isoforms on neurogenesis. We used ApoE knock-in mice of different ages and sex, and quantified newborn cells in the hippocampus by flow cytometry. Young adult ApoE4 mice (10-12 week-old) from both sexes displayed reduced neurogenesis compared with wild-types and the other genotypes. In addition, young adult ApoE2 female mice showed improved hippocampal progenitor cell proliferation. In older mice (1 year), hippocampal neurogenesis was globally decreased, particularly in females, and the difference between ApoE4 and the other genotypes observed in young animals disappeared for the two sexes, except for aged ApoE3 females. Indeed, a surprising protective effect of the ApoE3 genotype was observed in aged females. Our study highlights the role of ApoE in neurogenesis, and shows for the first time an early inequality between the ApoE genotypes. The reduced neurogenesis observed for the ApoE4 genotype and the improved results obtained in young ApoE2 females support the idea of a difference in the balance between neuronal birth and death modulated by the ApoE polymorphism in young animals. The maintenance of this balance and its modulation can influence pathophysiological mechanisms predisposing to neurodegenerative diseases like AD.

Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature.

Most cases of type III hyperlipoproteinemia are accounted for by apolipoprotein E2 (apoE2) homozygotes, a genetic mutation of apoE (Arg158Cys). Glomerulopathy with homozygous apoE2 is rare and characterized by marked foam cell infiltration in the glomerular capillaries and mesangium. Here, we report 3 cases of apoE2 homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 cases were middle-aged or elderly males complicated with diabetes for at least a decade. The kidney biopsies showed massive foam cell infiltration in the glomerular capillaries and expanded mesangium accompanied by histological findings of diabetic glomerulosclerosis. The lipid profiles showed type III hyperlipoproteinemia and phenotypic/genetic analyses revealed homozygosity of apoE2. Two of the cases showed nephrotic proteinuria and progressed to renal failure in 3 and 8 years after the diagnosis of kidney disease.

Gravidade da lesão angiográfica coronariana e polimorfismo da APOE nas síndromes coronarianas agudas / Severidad de la lesión angiográfica coronaria y polimorfismo de la APOE en los síndromes coronarios agudos / Severity of angiographic coronary obstruction and the apolipoprotein E polymorphism in acute coronary syndromes

FUNDAMENTO: Existem evidências de associação entre o polimorfismo da apolipoproteína E (APOE) e a doença coronariana, entretanto há controvérsias. OBJETIVO: Avaliar a associação entre o número de vasos coronarianos acometidos por obstrução significativa definida por angiografia, o polimorfismo da APOE e as variáveis clínicas. MÉTODOS: Estudo transversal multicêntrico que envolveu 207 pacientes (138 homens) com síndrome coronariana aguda (SCA) em Niterói (RJ - Brasil), os quais realizaram angiografia coronariana e determinação do genótipo para o polimorfismo APOE *2*3*4, pelo método de Restriction Fragment Length Polymorphism (RFLP). RESULTADOS: A frequência dos alelos APOE *2 foi de 6,8 por cento, *3 foi de 82,5 por cento, e *4 foi de 10,7 por cento. Quanto ao número de vasos lesados, 27 por cento dos pacientes apresentavam obstrução uniarterial, 33,8 por cento, biarterial, e 39,1 por cento, triarterial ou de tronco da coronária esquerda. O grau de lesão multivascular não se relacionou com a presença do alelo *4 (p = 0,78), mas com a idade > 55 anos (p = 0,025), o ex-tabagismo (p = 0,004) e a dislipidemia (p = 0,05) na análise multivariada e com doença arterial coronariana prévia (p = 0,05), diabete (p = 0,038) e síndrome metabólica (p = 0,021) na análise univariada. A prevalência de dislipidemia, diabete e hipertensão arterial sistêmica (HAS) foi elevada em relação a estudos semelhantes, com aumento progressivo da prevalência de HAS (p = 0,59) e de diabete (p = 0,06), de acordo com o número de vasos lesados. CONCLUSÃO: O polimorfismo da APOE não se associou ao número de vasos coronarianos com obstrução significativa em qualquer faixa etária. Por outro lado, a idade > 55 anos, o ex-tabagismo e a dislipidemia associaram-se à lesão multivascular.

BACKGROUND: There is evidence of the association between the apolipoprotein E (APOE) and coronary disease; however, there are controversies. OBJECTIVE: To evaluate the association between the number of coronary vessels with significant obstruction defined by angiography, the APOE polymorphism and clinical variables. METHODS: This was a cross-sectional, multicenter study with 207 patients (138 men), with acute coronary syndrome (ACS), in the city of Niteroi, state of Rio de Janeiro, Brazil, who underwent coronary angiography and genotype determination for the APOE *2*3*4 polymorphism by the Restriction Fragment Length Polymorphism (RFLP) method. RESULTS: The frequency of the alleles was APOE *2 - 6.8 percent, *3 - 82.5 percent, *4 - 10.7 percent. Regarding the number of affected vessels, 27 percent of patients presented monoarterial obstruction, 33.8 percent biarterial and 39.1 percent triarterial and/or left coronary trunk. The degree of multivascular lesion did not correlate with the presence of the *4 allele (p= 0.78), but with age > 55 years (p=0.025), being an ex-smoker (p=0.004) and dyslipidemia (p=0.05) at the multivariate analysis and also with previous coronary artery disease (CAD) (p=0.05), diabetes (p=0.038) and metabolic syndrome (p=0.021) at the univariate analysis. The prevalence of dyslipidemia, diabetes and systemic arterial hypertension (SAH) was elevated regarding similar studies, with progressive increases in the prevalence of SAH (p=0.59) and diabetes (p=0.06), according to the number of affected vessels. CONCLUSION: The APOE polymorphism was not associated with the number of coronary vessels with significant obstruction at any age range. On the other hand, age > 55 years, being an ex-smoker and dyslipidemia associated with the multivascular lesion.

FUNDAMENTO: Hay evidencias de asociación entre el polimorfismo de la apolipoproteína E (APOE) y la enfermedad coronaria, sin embargo hay controversias. OBJETIVO: Evaluar la asociación entre el número de vasos coronarios afectados por obstrucción significativa definida por angiografía, el polimorfismo de la APOE y las variables clínicas. MÉTODOS: Estudio transversal multicéntrico que implicó a 207 pacientes (138 varones) con síndrome coronario agudo (SCA) en la ciudad de Niterói (RJ - Brasil), los que realizaron angiografía coronaria, y determinación del genotipo para el polimorfismo APOE *2*3*4 mediante el método de Restriction Fragment Length Polymorphism (RFLP). RESULTADOS: La frecuencia de los alelos APOE *2 fue del 6,8 por ciento, *3 fue del 82,5 por ciento, y *4 fue del 10,7 por ciento. En cuanto al número de vasos lesionados, el 27 por ciento de los pacientes presentaban obstrucción uniarterial, el 33,8 por ciento, biarterial, y el 39,1 por ciento, triarterial o de tronco de la coronaria izquierda. El grado de lesión multivascular no se relacionó con la presencia del alelo *4 (p = 0,78), sino con la edad > 55 años (p = 0,025), el ex tabaquismo (p = 0,004) y la dislipidemia (p = 0,05) en el análisis multivariado y con la enfermedad arterial coronaria previa (p = 0,05), la diabetes (p = 0,038) y el síndrome metabólico (p = 0,021) en el análisis univariado. La prevalencia de dislipidemia, diabetes e hipertensión arterial sistémica (HAS) fue elevada con relación a estudios semejantes, con aumento progresivo de la prevalencia de HAS (p = 0,59) y de diabetes (p = 0,06), según el número de vasos lesionados. CONCLUSIÓN: El polimorfismo de la APOE no se asoció al número de vasos coronarios con obstrucción significativa en cualquier grupo de edad. Por otro lado, la edad > 55 años, el ex tabaquismo y la dislipidemia se asociaron a la lesión multivascular.