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1
Tai, Leon M., Katherine L. Youmans, Lisa Jungbauer, Chunjiang Yu, and Mary Jo LaDu. "Introducing HumanAPOEinto AβTransgenic Mouse Models." International Journal of Alzheimer's Disease 2011 (2011): 1–9. http://dx.doi.org/10.4061/2011/810981.
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Apolipoprotein E (apoE) and apoE/amyloid-β(Aβ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type,apoE−/−mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology,apoE−/−mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice withapoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβpathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβpathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve.
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Vecchio, Filomena Lo, Paola Bisceglia, Bruno Pietro Imbimbo, Madia Lozupone, Raffaela Rita Latino, Emanuela Resta, Maurizio Leone, et al. "Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?" Therapeutic Advances in Chronic Disease 13 (January 2022): 204062232210816. http://dx.doi.org/10.1177/20406223221081605.
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Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE ( APOE) have a fourfold greater risk of developing Alzheimer’s disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.
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James, Niaya, Oyinkansola Shonde, Nahdia Jones, Verona E. Mulgrave, G. William Rebeck, and Joanne Allard. "Impact of APOE Genotype on Diet-induced Mitochondrial Adaptations in Mouse Skeletal Muscle." Innovation in Aging 5, Supplement_1 (December 1, 2021): 971. http://dx.doi.org/10.1093/geroni/igab046.3496.
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Abstract Apolipoprotein E (APOE), a component of lipoproteins that facilitates cholesterol transportation, has three variants in the human genome: APOE2, E3, and E4. Prior research found that carriers of APOE4 are more susceptible to developing Alzheimer's disease (AD) and other brain disorders than those who possess other APOE alleles, and that these carriers are also predisposed to mitochondrial impairment– an early characteristic of neuronal dysfunction. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1ɑ) is a major biomarker for mitochondrial biogenesis and function and cytochrome c oxidase subunit IV (COX4) is the terminal enzyme of the mitochondrial respiratory chain. Decreased measures of these proteins indicate reduced mitochondrial function. Aside from genetic inheritance, lifestyle factors such as diet and exercise significantly impact one’s risk for mitochondrial dysfunction and AD. In these studies, we examined the impact of APOE variance on physiological adaptations induced by either exercise or a high-fat diet, with a focus on biomarkers of mitochondrial function. Western blots were used to measure COX4 and PGC-1ɑ levels in skeletal muscle tissue from female APOE3 and APOE4 knock-in transgenic mice. Based on performance on a motorized rotating rod and voluntary wheel-running, we deduced that female APOE4 mice exhibit reduced motor coordination and activity relative to APOE3 mice. APOE4 mice also had reduced COX4 levels that were increased by the high-fat diet. In contrast, COX4 levels in APOE3 mice were reduced in the high-fat diet group. Our data show that diet and APOE genotype interact to produce adaptations in mitochondrial proteins in skeletal muscle.
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Watson, Yassin, Brenae Nelson, Jamie Hernandez Kluesner, Caroline Tanzy, Shreya Ramesh, Zoey Patel, Kaci Hernandez Kluesner, Anita Singh, Vibha Murthy, and Cassie S. Mitchell. "Aggregate Trends of Apolipoprotein E on Cognition in Transgenic Alzheimer’s Disease Mice." Journal of Alzheimer's Disease 83, no. 1 (August 31, 2021): 435–50. http://dx.doi.org/10.3233/jad-210492.
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Background: Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer’s disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord. Objective: Analysis of 31 peer-reviewed AD APOE mouse publications (n = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition. Methods: T-tests with Bonferroni correction (significance = p < 0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t–) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t–, t0), mouse age, and mouse gender (male = g_m; female = g_f, mixed gender = g_mi). Results: KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t–, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023]. Conclusion: APOE3, age, and male gender was most important for predicting superior mouse cognitive performance.
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Sheng, Huaxin, Daniel T. Laskowitz, Ellen Bennett, Donald E. Schmechel, Robert D. Bart, Ann M. Saunders, Robert D. Pearlstein, Allen D. Roses, and David S. Warner. "Apolipoprotein E Isoform-Specific Differences in Outcome from Focal Ischemia in Transgenic Mice." Journal of Cerebral Blood Flow & Metabolism 18, no. 4 (April 1998): 361–66. http://dx.doi.org/10.1097/00004647-199804000-00003.
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Apolipoprotein E (apoE), a 34-kD glycosylated lipid-binding protein, is expressed as three common isoforms in humans (E2, E3, or E4). Clinical evidence suggests that the apoE genotype (APOE) may be a risk factor for poor outcome after acute central nervous system injury. This was examined further in transgenic mice constructed with the human APOE3 or APOE4 gene under the control of human promoter and tissue expression elements. Presence of human apoE3 and apoE4 proteins in brains of human APOE homozygous transgenic mice was confirmed by Western blotting. APOE3 (n = 12) and APOE4 (n = 10) mice underwent 60 minutes of middle cerebral artery occlusion. After 24-hour recovery, infarct size was measured. Infarct volumes (mean ± standard deviation) were smaller in the APOE3 group (cortex: APOE3 = 18 ± 4 mm3; APOE4 = 30 ± 11 mm3, P = 0.04; subcortex: APOE3 = 12 ± 4 mm3; APOE4 = 18 ± 4 mm3, P = 0.003). Hemiparesis was less severe in APOE3 mice ( P = 0.02). These data indicate that human isoform-specific effects of apoE are relevant to acute pathomechanisms of focal ischemic brain damage when examined in the mouse. APOE transgenic mice may provide an appropriate model to examine the mechanistic basis for the differential effects of human apoE isoforms in acute central nervous system injury.
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Zhao, Na, Olivia N. Attrebi, Yingxue Ren, Wenhui Qiao, Berkiye Sonustun, Yuka A. Martens, Axel D. Meneses, et al. "APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid." Science Translational Medicine 12, no. 529 (February 5, 2020): eaay1809. http://dx.doi.org/10.1126/scitranslmed.aay1809.
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The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.
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Zhang, Xin, Long Wu, Russell H. Swerdlow, and Liqin Zhao. "Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease." Cells 12, no. 3 (January 25, 2023): 410. http://dx.doi.org/10.3390/cells12030410.
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Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer’s disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.
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Dafnis, Ioannis, Christina Raftopoulou, Christina Mountaki, Evgenia Megalou, Vassilis I. Zannis, and Angeliki Chroni. "ApoE isoforms and carboxyl-terminal-truncated apoE4 forms affect neuronal BACE1 levels and Aβ production independently of their cholesterol efflux capacity." Biochemical Journal 475, no. 10 (May 31, 2018): 1839–59. http://dx.doi.org/10.1042/bcj20180068.
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The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) initiates the production of amyloid-β peptide (Aβ), which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect Aβ metabolism. Cholesterol homeostasis is maintained in the brain by apolipoprotein E (apoE). The apoE4 isoform constitutes the major risk factor for AD. Here, we investigated the effect of apoE forms on Aβ generation and on BACE1 levels. We also examined the potential involvement in these processes of cholesterol transporters ABCG1 and ABCG4 or the lipoprotein receptor SR-BI, which are implicated in cholesterol efflux to apoE. It was found that reconstituted lipoprotein-associated apoE isoforms promoted the increase of Aβ production and oligomerization and of BACE1 levels in human neuroblastoma SK-N-SH cells, with an apoE4 ≥ apoE3 > apoE2 potency rank order. Progressive carboxyl-terminal apoE4 deletions between residues 230–299 decreased the protein's ability to increase BACE1, while further truncations up to residue 166 prevented apoE4 from increasing BACE1 and Aβ levels in SK-N-SH and primary mouse neuronal cells. ABCG1, but not ABCG4 or SR-BI, moderately increased Aβ production and BACE1 levels in SK-N-SH cells. All apoE forms affected Aβ production/oligomerization and BACE1 levels in a pattern that did not follow that of their capacity to promote ABCG1, ABCG4 or SR-BI-mediated cholesterol efflux. Overall, our data indicate that apoE-containing lipoprotein particles can have a direct effect on BACE1 levels and Aβ secretion and possibly contribute to AD pathogenetic processes, independently of their capacity to promote cholesterol efflux.
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Demby, Tamar, G. William Rebeck, Christopher Albanese, Olga C. Rodriguez, Yichien Lee, and Jeanne Mandelblatt. "3367 A Mouse Model of APOE Genotype in Chemotherapy Related Cognitive Impairment." Journal of Clinical and Translational Science 3, s1 (March 2019): 1. http://dx.doi.org/10.1017/cts.2019.6.
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OBJECTIVES/SPECIFIC AIMS: Chemotherapy-related cognitive impairment (CRCI) affects 15-35% of breast cancer survivors and constitutes a significant challenge for survivor quality of life. Among older breast cancer survivors who received chemotherapy treatment, carriers of at least one ɛ4 allele of the APOE gene, which encodes apolipoprotein E, are at higher risk for developing CRCI than non-carriers. APOE4 is well characterized as the strongest genetic risk factor for Alzheimer’s disease, but how it contributes to CRCI is not yet understood, and no animal models of APOE genotype and CRCI have yet been established. To better understand how APOE4 acts as a risk factor for CRCI, we used APOE targeted replacement (TR) mice to develop a model of its effects on cognition following treatment with doxorubicin, a chemotherapy drug commonly used in breast cancer treatment. METHODS/STUDY POPULATION: Twelve-to-thirteen month old APOE3 and APOE4 targeted replacement mice expressing human APOE3 or human APOE4 under control of the endogenous murine promoter were treated with 10 mg/kg doxorubicin or equivolume saline given via two IP injections spaced one week apart. One week post-treatment, mice were tested using Open Field and Elevated Zero apparatuses to assess baseline locomotive activity and anxiety and exploratory behaviors. Five weeks post-treatment, mice were assessed using the Barnes Maze over four days of training trials and one 72 hour memory probe. RESULTS/ANTICIPATED RESULTS: We found no differences in Open Field and Elevated Zero behavior, indicating limited influence of doxorubicin treatment on locomotive and anxiety behaviors in both genotypes. During Barnes Maze training, APOE4 mice treated with doxorubicin showed increased latency compared to untreated APOE4 mice as well as treated and untreated APOE3 mice, indicating deficiencies in spatial learning. In APOE3 mice, no differences in performance were seen between doxorubicin-treated and untreated mice (n = 15-16/group, p <.0001). DISCUSSION/SIGNIFICANCE OF IMPACT: These results indicate that APOE4 targeted replacement mice have specific cognitive vulnerabilities to doxorubicin treatment that can be reliably detected using the Barnes Maze assessment. Future directions include experiments to determine how other chemotherapy drugs or drug combinations impact cognition of APOE4 mice. Ultimately this model may be used to assess preventive measures or therapies for CRCI in the vulnerable APOE4 carrier population with the ability to validate cognitive impacts of these interventions.
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Staurenghi, Erica, Valerio Leoni, Marco Lo Iacono, Barbara Sottero, Gabriella Testa, Serena Giannelli, Gabriella Leonarduzzi, and Paola Gamba. "ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis." Antioxidants 11, no. 11 (November 1, 2022): 2168. http://dx.doi.org/10.3390/antiox11112168.
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The strongest genetic risk factor for sporadic Alzheimer’s disease (AD) is the presence of the ε4 allele of the apolipoprotein E (ApoE) gene, the major apolipoprotein involved in brain cholesterol homeostasis. Being astrocytes the main producers of cholesterol and ApoE in the brain, we investigated the impact of the ApoE genotype on astrocyte cholesterol homeostasis. Two mouse astrocytic cell lines expressing the human ApoE3 or ApoE4 isoform were employed. Gas chromatography–mass spectrometry (GC-MS) analysis pointed out that the levels of total cholesterol, cholesterol precursors, and various oxysterols are altered in ApoE4 astrocytes. Moreover, the gene expression analysis of more than 40 lipid-related genes by qRT-PCR showed that certain genes are up-regulated (e.g., CYP27A1) and others down-regulated (e.g., PPARγ, LXRα) in ApoE4, compared to ApoE3 astrocytes. Beyond confirming the significant reduction in the levels of PPARγ, a key transcription factor involved in the maintenance of lipid homeostasis, Western blotting showed that both intracellular and secreted ApoE levels are altered in ApoE4 astrocytes, as well as the levels of receptors and transporters involved in lipid uptake/efflux (ABCA1, LDLR, LRP1, and ApoER2). Data showed that the ApoE genotype clearly affects astrocytic cholesterol homeostasis; however, further investigation is needed to clarify the mechanisms underlying these differences and the consequences on neighboring cells. Indeed, drug development aimed at restoring cholesterol homeostasis could be a potential strategy to counteract AD.
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Mhatre-Winters, Isha, Aseel Eid, Yoonhee Han, Kim Tieu, and Jason R. Richardson. "Sex and APOE Genotype Alter the Basal and Induced Inflammatory States of Primary Astrocytes from Humanized Targeted Replacement Mice." ASN Neuro 15 (January 2023): 175909142211445. http://dx.doi.org/10.1177/17590914221144549.
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Apolipoprotein E4 (APOE4) genotype and sex are significant risk factors for Alzheimer's disease (AD), with females demonstrating increased risk modulated by APOE genotype. APOE is predominantly expressed in astrocytes, however, there is a lack of comprehensive assessments of sex differences in astrocytes stratified by APOE genotype. Here, we examined the response of mixed-sex and sex-specific neonatal APOE3 and APOE4 primary mouse astrocytes (PMA) to a cytokine mix of IL1b, TNFa, and IFNg. Pro-inflammatory and anti-inflammatory cytokine profiles were assessed by qRT-PCR and Meso Scale Discovery multiplex assay. Mixed-sex APOE4 PMA were found to have higher basal messenger RNA expression of several pro-inflammatory cytokines including Il6, Tnfa, Il1b, Mcp1, Mip1a, and Nos2 compared to APOE3 PMA, which was accompanied by increased levels of these secreted cytokines. In sex-specific cultures, basal expression of Il1b, Il6, and Nos2 was 1.5 to 2.5 fold higher in APOE4 female PMA compared to APOE4 males, with both being higher than APOE3 PMA. Similar results were found for secreted levels of these cytokines. Together, these findings indicate that APOE4 genotype and female sex, contribute to a greater inflammatory response in primary astrocytes and these data may provide a framework for investigating the mechanisms contributing to genotype and sex differences in AD-related neuroinflammation.
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Huang, Yadong. "Roles of apolipoprotein E4 (ApoE4) in the pathogenesis of Alzheimer's disease: lessons from ApoE mouse models." Biochemical Society Transactions 39, no. 4 (July 20, 2011): 924–32. http://dx.doi.org/10.1042/bst0390924.
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ApoE4 (apolipoprotein E4) is the major known genetic risk factor for AD (Alzheimer's disease). In most clinical studies, apoE4 carriers account for 65–80% of all AD cases, highlighting the importance of apoE4 in AD pathogenesis. Emerging data suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to AD in multiple ways either independently or in combination with other factors, such as Aβ (amyloid β-peptide) and tau. Many apoE mouse models have been established to study the mechanisms underlying the pathogenic actions of apoE4. These include transgenic mice expressing different apoE isoforms in neurons or astrocytes, those expressing neurotoxic apoE4 fragments in neurons and human apoE isoform knock-in mice. Since apoE is expressed in different types of cells, including astrocytes and neurons, and in brains under diverse physiological and/or pathophysiological conditions, these apoE mouse models provide unique tools to study the cellular source-dependent roles of apoE isoforms in neurobiology and in the pathogenesis of AD. They also provide useful tools for discovery and development of drugs targeting apoE4's detrimental effects.
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Zhu, Li, Minghao Zhong, Gregory A. Elder, Mary Sano, David M. Holtzman, Sam Gandy, Christopher Cardozo, Vahram Haroutunian, Nikolaos K. Robakis, and Dongming Cai. "Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis." Proceedings of the National Academy of Sciences 112, no. 38 (September 8, 2015): 11965–70. http://dx.doi.org/10.1073/pnas.1510011112.
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The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer’s disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.
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Mori, Takashi, Terrence Town, Mariko Kobayashi, Jun Tan, Shinobu C. Fujita, and Takao Asano. "Augmented Delayed Infarct Expansion and Reactive Astrocytosis after Permanent Focal Ischemia in Apolipoprotein E4 Knock-In Mice." Journal of Cerebral Blood Flow & Metabolism 24, no. 6 (June 2004): 646–56. http://dx.doi.org/10.1097/01.wcb.0000120787.53851.a4.
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Using homozygous human apolipoprotein E2 (apoE2) (2/2)-, apoE3 (3/3)-, or apoE4 (4/4)-knock-in (KI) mice, we aimed to examine whether an apoE isoform-specific exacerbation of delayed infarct expansion occurs after permanent middle cerebral artery occlusion (pMCAO). Compared with 2/2- or 3/3-KI mice, 4/4-KI mice exhibited significantly larger infarct volumes and worse neurologic deficits after pMCAO, with no significant differences between the latter two groups. Infarct volume in 4/4-KI mice was significantly increased from 1 to 5 days after pMCAO, whereas that in 2/2- or 3/3-KI mice was not significantly altered. DNA fragmentation in the peri-infarct area as detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatenick end-labeling was increased to a similar degree in all of the KI mice by 5 days after pMCAO, with no significant differences among the mouse groups. At every time-point examined, human apoE was most markedly expressed in the peri-infarct area, with similar immunoreactivity among the three lines of KI mice. The glial fibrillary acidic protein immunoreactive burden in the peri-infarct area was progressively increased through 7 days in 4/4-KI mice, but not in 2/2- or 3/3-KI mice. Taken together, these data show that the apoE4 isoform acts to aggravate delayed infarct expansion and peri-infarct reactive astrocytosis during the subacute phase of pMCAO in genetically engineered apoE-KI mice.
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McLean, John W., Avnish Bhattrai, Francesca Vitali, Adam C. Raikes, Jean-Paul L. Wiegand, and Roberta Diaz Brinton. "Contributions of sex and genotype to exploratory behavior differences in an aged humanized APOE mouse model of late-onset Alzheimer's disease." Learning & Memory 29, no. 9 (September 2022): 321–31. http://dx.doi.org/10.1101/lm.053588.122.
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Age, genetics, and chromosomal sex have been identified as critical risk factors for late-onset Alzheimer's disease (LOAD). The predominant genetic risk factor for LOAD is the apolipoprotein E ε4 allele (APOE4), and the prevalence of LOAD is higher in females. However, the translational validity of APOE4 mouse models for AD-related cognitive impairment remains to be fully determined. The present study investigated the role of both sex and genotype on learning and memory in aged, humanized APOE knock-in mice. Aged (23.27 mo ± 1.21 mo; 39 male/37 female) APOE3/3, APOE3/4, and APOE4/4 mice performed a novel object recognition (NOR) assay. Task-related metrics were analyzed using two-way sex by genotype ANOVAs. Sex differences were more prominent relative to APOE genotype. Prior to NOR, female mice exhibited thigmotaxic center zone avoidance during the open field task relative to males, regardless of genotype. Within object familiarization and NOR tasks, females had greater object interaction and locomotion. Interestingly, only APOE4/4 females on average recognized the novel object. These results suggest that APOE4, although strongly related to LOAD pathogenesis, does not drive cognitive decline in the absence of other risk factors even in very aged mice. Chromosomal sex is a key driver of behavioral phenotypes and thus is a critical variable for translatability of interventions designed to preserve learning and memory in animal models of LOAD. Last, there was a very high degree of variability in behavioral performance across APOE genotypes. A cluster analysis of the behavioral data revealed a low-activity and a high-activity cluster. APOE4 carriers were overrepresented in the low-activity cluster, while male:female distributions did not differ. Collectively, the behavioral data indicate that chromosomal sex has the greatest impact on behavioral phenotype, and APOE4 carrier status may confer greater risk for cognitive decline in some animals.
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Chang, Ya-Hsuan, Jared Hoffman, Lucille Yanckello, Scott McCulloch, Penghui Lin, Andrew Lane, George Chlipala, Stefan Green, and Ai-Ling Lin. "Apolipoprotein E Genotype-Dependent Nutrigenetic Effects to Prebiotic Inulin for Reducing Risk for Alzheimer's Disease in a Mouse Model." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1197. http://dx.doi.org/10.1093/cdn/nzaa057_013.
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Abstract Objectives Apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer's disease (AD). Cognitively normal APOE4 carriers show an early decline in brain metabolic functions and gut microbiome dysbiosis before the onset of AD compared to APOE3 carriers. Our laboratory previously found that inulin, a prebiotic, is effective to restore metabolic functions and gut microbiome balance, and thus reduce risk for AD in an ApoE4 mouse model. However, whether the responses to the inulin are APOE allele-dependent remains unknown. Therefore, our objective was to identify whether inulin would differently contribute to metabolic and gut microbiome changes due to APOE genotypes. Methods We fed 3-month-old asymptomatic ApoE3 (E3FAD) and ApoE4 (E4FAD) mice prebiotic inulin or cellulose as a control for 4 months (N = 60; Male: Female = 1:1). After 4 months, we used magnetic resonance spectroscopy to measure in vivo brain scyllo-inositol level, a compound that has been demonstrated to inhibit amyloid β aggregation. We collected the fecal samples for gut microbiome sequencing, and cecal and blood samples for metabolomic profiling. Results Inulin induced scyllo-inositol in hippocampus of the brain with a higher level in E4FAD mice. Inulin increased blood metabolites in tryptophan and tyrosine metabolic pathways that enhance nervous system in E3FAD mice. It increased blood metabolites in pentose phosphate pathway and citric acid cycle that support nucleotides and nucleic acids biosynthesis and energy production in E4FAD mice. These alterations in hippocampus and blood showed inulin's impacts on systemic metabolism depending on mouse ApoE genotypes. Inulin enhanced short chain fatty acids in cecum with a greater increase in E3FAD mice. E3FAD mice showed more distinct gut microbiome patterns between inulin and control groups compared to E4FAD mice. Conclusions Inulin-induced systemic metabolism and gut microbiome changes are APOE genotype-dependent. Future studies can design human interventions that may facilitate the guide of personalized nutrition in AD prevention. Funding Sources This research was supported by grants from NIH, NIH/CTSA, and American Federation for Aging Research to A-LL and NIH/NIDDK to JDH and LMY. The 7T ClinScan small animal MRI scanner was funded by the S10 NIH Shared Instrumentation Program Grant.
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Braunersreuther, Vincent, Fabienne Burger, Sébastien Lenglet, Graziano Pelli, Federico Carbone, Rodrigo Fraga-Silva, Nikolaos Stergiopulos, et al. "Anti-apoA-1 auto-antibodies increase mouse atherosclerotic plaque vulnerability, myocardial necrosis and mortality triggering TLR2 and TLR4." Thrombosis and Haemostasis 114, no. 08 (2015): 410–22. http://dx.doi.org/10.1160/th14-12-1039.
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SummaryAuto-antibodies to apolipoprotein A-1 (anti-apoA-1 IgG) were shown to promote inflammation and atherogenesis, possibly through innate immune receptors signalling. Here, we aimed at investigating the role of Toll-like receptors (TLR) 2 and 4 on anti-apoA-1 IgG-induced athero-sclerotic plaque vulnerability, myocardial necrosis and mortality in mice. Adult male apolipoprotein E knockout (ApoE)-/- (n=72), TLR2-/-ApoE-/- (n=36) and TLR4-/-Apo-/- (n=28) mice were intravenously injected with 50 µg/mouse of endotoxin-free polyclonal anti-apoA-1 IgG or control isotype IgG (CTL IgG) every two weeks for 16 weeks. Atherosclerotic plaque size and vulnerability were assessed by histology. Myocardial ischaemia and necrosis, respectively, were determined by electrocardiographic (ECG) changes assessed by telemetry and serum troponin I (cTnI) measurements. Impact on survival was assessed by Kaplan-Meier analyses. In ApoE-/- mice, anti-apoA-1 IgG passive immunisation enhanced histological features of athero-sclerotic plaque vulnerability (increase in neutrophil and MMP-9 and reduction in collagen content), induced a substantial cTnI elevation (p=0.001), and increased mortality rate by 23 % (LogRank, p=0.04) when compared to CTL IgG. On a subgroup of ApoE-/- mice equipped with telemetry (n=4), a significant ST-segment depression was noted in anti-apoA-1 IgG-treated mice when compared to CTL IgG recipients (p< 0.001), and an acute ST-segment elevation myocardial infarction preceding mouse death was observed in one case. The deleterious effects of anti-apoA-1 IgG on atherosclerotic plaque vulnerability, myocardial necrosis and death were partially reversed in TLR2-/-ApoE-/- and TLR4-/-ApoE-/- backgrounds. In conclusion, anti-apoA-1 auto-antibodies seem to be active mediators of atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in mice through TLR2- and TLR4-mediated pathways.
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Yang, Hong, Ningya Zhang, Emmanuel Okoro, and Zhongmao Guo. "Transport of Apolipoprotein B-Containing Lipoproteins through Endothelial Cells Is Associated with Apolipoprotein E-Carrying HDL-Like Particle Formation." International Journal of Molecular Sciences 19, no. 11 (November 14, 2018): 3593. http://dx.doi.org/10.3390/ijms19113593.
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Passage of apolipoprotein B-containing lipoproteins (apoB-LPs), i.e., triglyceride-rich lipoproteins (TRLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs), through the endothelial monolayer occurs in normal and atherosclerotic arteries. Among these lipoproteins, TRLs and IDLs are apoE-rich apoB-LPs (E/B-LPs). Recycling of TRL-associated apoE has been shown to form apoE-carrying high-density lipoprotein (HDL)-like (HDLE) particles in many types of cells. The current report studied the formation of HDLE particles by transcytosis of apoB-LPs through mouse aortic endothelial cells (MAECs). Our data indicated that passage of radiolabeled apoB-LPs, rich or poor in apoE, through the MAEC monolayer is inhibited by filipin and unlabeled competitor lipoproteins, suggesting that MAECs transport apoB-LPs via a caveolae-mediated pathway. The cholesterol and apoE in the cell-untreated E/B-LPs, TRLs, IDLs, and LDLs distributed primarily in the low-density (LD) fractions (d ≤ 1.063). A substantial portion of the cholesterol and apoE that passed through the MAEC monolayer was allotted into the high-density (HD) (d > 1.063) fractions. In contrast, apoB was detectable only in the LD fractions before or after apoB-LPs were incubated with the MAEC monolayer, suggesting that apoB-LPs pass through the MAEC monolayer in the forms of apoB-containing LD particles and apoE-containing HD particles.
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Guardia-Escote, Laia, Jordi Blanco, Pia Basaure, Judit Biosca-Brull, Rikst Nynke Verkaik-Schakel, Maria Cabré, Fiona Peris-Sampedro, et al. "Sex and Exposure to Postnatal Chlorpyrifos Influence the Epigenetics of Feeding-Related Genes in a Transgenic APOE Mouse Model: Long-Term Implications on Body Weight after a High-Fat Diet." International Journal of Environmental Research and Public Health 18, no. 1 (December 29, 2020): 184. http://dx.doi.org/10.3390/ijerph18010184.
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Developmental exposure to toxicants and diet can interact with an individual’s genetics and produce long-lasting metabolic adaptations. The different isoforms of the apolipoprotein E (APOE) are an important source of variability in metabolic disorders and influence the response to the pesticide chlorpyrifos (CPF). We aimed to study the epigenetic regulation on feeding control genes and the influence of postnatal CPF exposure, APOE genotype, and sex, and how these modifications impact on the metabolic response to a high-fat diet (HFD). Both male and female apoE3- and apoE4-TR mice were exposed to CPF on postnatal days 10–15. The DNA methylation pattern of proopiomelanocortin, neuropeptide Y, leptin receptor, and insulin-like growth factor 2 was studied in the hypothalamus. At adulthood, the mice were given a HFD for eight weeks. The results highlight the importance of sex in the epigenetic regulation and the implication of CPF treatment and APOE genotype. The body weight progression exhibited sex-dimorphic differences, apoE4-TR males being the most susceptible to the effects induced by CPF and HFD. Overall, these results underscore the pivotal role of sex, APOE genotype, and developmental exposure to CPF on subsequent metabolic disturbances later in life and show that sex is a key variable in epigenetic regulation.
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Rijpma, A., D. Jansen, I. A. C. Arnoldussen, X. T. Fang, M. Wiesmann, M. P. C. Mutsaers, P. J. Dederen, C. I. F. Janssen, and A. J. Kiliaan. "Sex Differences in Presynaptic Density and Neurogenesis in Middle-Aged ApoE4 and ApoE Knockout Mice." Journal of Neurodegenerative Diseases 2013 (January 27, 2013): 1–9. http://dx.doi.org/10.1155/2013/531326.
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Atherosclerosis and apolipoprotein E ε4 (APOE4) genotype are risk factors for Alzheimer’s disease (AD) and cardiovascular disease (CVD). Sex differences exist in prevalence and manifestation of both diseases. We investigated sex differences respective to aging, focusing on cognitive parameters in apoE4 and apoE knockout (ko) mouse models of AD and CVD. Presynaptic density and neurogenesis were investigated immunohistochemically in male and female apoE4, apoE ko, and wild-type mice. Middle-aged female apoE4 mice showed decreased presynaptic density in the inner molecular layer of the dentate gyrus of the hippocampus. Middle-aged female apoE ko mice showed a trend towards increased neurogenesis in the hippocampus compared with wild-type mice. No differences in these parameters could be observed in middle-aged male mice. Specific harmful interactions between apoE4 and estrogen could be responsible for decreased presynaptic density in female apoE4 mice. The trend of increased neurogenesis found in female apoE ko mice supports previous studies suggesting that temporarily increased amount of synaptic contacts and/or neurogenesis is a compensatory mechanism for synaptic failure. To our knowledge, no other studies investigating presynaptic density in aging female apoE4 or apoE ko mice are available. Sex-specific differences between APOE genotypes could account for some sex differences in AD and CVD.
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wang, chao, Aimin Li, Rebecca Spellman, Xin Bao, Nathan Scott, Melissa Manis, Mary Beth Finn, et al. "Effects of human LDLR overexpression on apoE-related tau pathology and brain dysfunction." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 64.6. http://dx.doi.org/10.4049/jimmunol.204.supp.64.6.
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Abstract ApoE4 is the strongest genetic risk factor for late-onset Alzheimer Disease. It has been reported that apoE isoforms directly affect tauopathy and tau-mediated neurodegeneration in P301S tau transgenic mice expressing different human apoE isoforms, with apoE4 resulting in markedly increased tau-mediated neurodegeneration and the absence of apoE being marked protective against neurodegeneration. In the brain, low-density lipoprotein receptor (LDLR) is one of the main apoE receptors that regulates apoE levels, but LDLR has very few identified ligands compared to other apoE receptors. LDLR overexpression in the brain can dramatically lower apoE and Aβ levels, as well as decrease Aβ accumulation and deposition. Therefore, we propose to evaluate whether AAV-mediated overexpression of human LDLR (hLDLR) is an efficient way to reduce apoE levels, tau pathology, and neurodegeneration. To study the effect of LDLR overexpression on apoE4-related tau pathology and neurodegeneration, P301S Tau/ApoE4 (TE4) male mice received bilateral intracerebroventricular injection with AAV expressing hLDLR or GFP-control, starting before the onset of tau pathology development. Brains were isolated after 9 month, divided into hemispheres, and analyzed by histological and biochemical techniques. Widespread expression of hLDLR throughout the brain was observed and apoE levels were significantly decreased. Furthermore, mouse nest-building impairment was rescued after hLDLR overexpression. Strikingly, there is a significant decrease in brain atrophy, phosphorylated tau deposition in TE4 mice overexpressing hLDLR. In summary, these data suggest that LDLR may be a promising target to lower apoE levels and decrease neurodegeneration.
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Provost, Pierre R., Eric Boucher, and Yves Tremblay. "Apolipoprotein A-I, A-II, C-II, and H expression in the developing lung and sex difference in surfactant lipids." Journal of Endocrinology 200, no. 3 (December 23, 2008): 321–30. http://dx.doi.org/10.1677/joe-08-0238.
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A sex difference in surfactant lipids is associated with a higher incidence of respiratory distress syndrome for males in cases of preterm birth. In animal models, the sex difference in surfactant lipids was shown to be androgen receptor-dependent. This report examines expression of apolipoprotein (apo)A-I, apoA-II, apoC-II, apoE, apoH, and lipoprotein lipase (LPL) by quantitative real-time PCR in pools of male and female fetal lung tissues from various mouse litters from gestation day (GD) 15.5 to 18.5, and in various adult tissues. Although the expression profiles of ApoA-I, ApoA-II, ApoC-II, and ApoH are complex, these genes are co-regulated and they all present a sex difference (P=0.0896, 0.0896, 0.0195, and 0.0607 respectively) with higher expression for females for several litters. Pulmonary expression of apoA-I, apoA-II, and apoH were specific to the developing lung. ApoE and LPL mRNAs showed a significant increase from GD 17.5 to 18.5. An increase in apoA-I-, apoA-II-, apoC-II-, and apoH-mRNA accumulation was observed from GD 16.5 to 17.5 in correlation with the emergence of mature type II pneumonocytes. These four apolipoprotein genes are co-regulated with type 2 and 5 17β-hydroxysteroid dehydrogenases, which are respectively involved in inactivation and synthesis of androgens. Finally, apoC-II was detected by immunohistochemistry in epithelial cells of the distal epithelium. Positive signals looking like secretory granules were located near the basal membrane. Our results are compatible with a role for apolipoproteins in lipid metabolism and transport in the developing lung in association with the sex difference in surfactant lipid synthesis.
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Liu, Min, David G. Kuhel, Ling Shen, David Y. Hui, and Stephen C. Woods. "Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 9 (November 1, 2012): R903—R908. http://dx.doi.org/10.1152/ajpregu.00219.2012.
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Apolipoprotein E (apoE) is a 34-kDa glycoprotein that is important in lipoprotein metabolism both peripherally and centrally. Because it is primarily produced in the liver, apoE observed in the brain or cerebrospinal fluid (CSF) could have originated in the periphery; i.e., circulating apoE may cross the blood-brain barrier (BBB) and/or enter CSF and be taken up by brain cells. To determine whether this occurs, a second-generation adenovirus encoding human apoE3 was administered intravenously (iv) to C57BL/6J mice, and the detection of human apoE3 in the CSF was used as a surrogate measure of central availability of this protein utilizing an improved method for sampling CSF from mice. This improved technique collects mouse CSF samples with a 92% success rate and consistently yields relatively large volumes of CSF with a very low rate of blood contamination, as determined by molecular assessment of apolipoprotein B, a plasma-derived protein that is absent in the central nervous system. Through this improved method, we demonstrated that in mice receiving the administered apoE3 adenovirus, human apoE3 was expressed at high levels in the liver, leading to high levels of human apoE3 in mouse plasma. In contrast, human apoE3 levels in the CSF, as assessed by a sensitive ELISA, were essentially undetectable in human apoE3 adenovirus-treated mice, and comparable to levels in LacZ adenovirus-treated control mice. These data indicate that apoE in the CSF cannot be derived from the plasma pool and, therefore, must be synthesized locally in the brain.
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Marottoli, Felecia M., Yuriko Katsumata, Kevin P. Koster, Riya Thomas, David W. Fardo, and Leon M. Tai. "Peripheral Inflammation, Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction." ASN Neuro 9, no. 4 (July 14, 2017): 175909141771920. http://dx.doi.org/10.1177/1759091417719201.
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Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 ( APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/−/ APOE+/+ (EFAD+)] and noncarriers [5xFAD−/−/ APOE+/+ (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.
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Liu, Ke, Bangzhu Chen, Fanwen Zeng, Gang Wang, Xin Wu, Yueshu Liu, Guiling Li, Jiarong Yan, and Shouquan Zhang. "ApoE/NOS3 Knockout Mice as a Novel Cardiovascular Disease Model of Hypertension and Atherosclerosis." Genes 13, no. 11 (November 1, 2022): 1998. http://dx.doi.org/10.3390/genes13111998.
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Hypertension is an independent risk factor for atherosclerosis. However, few models of hypertensive atherosclerosis have been established in medical research. In this study, we crossed the ApoE knockout (ApoE-KO; ApoE−/−) atherosclerotic mouse model with the NOS3 knockout (NOS3-KO; NOS3−/−) hypertensive mouse model to establish an ApoE/NOS3 double knockout (ApoE/NOS3-KO; ApoE/NOS3−/−) hypertensive atherosclerosis mouse model. We found that ApoE/NOS3−/− mice reproduced normally, had a blood pressure of 133.00 ± 3.85 mmHg, and developed hypertensive fundus retinopathy and hypertensive nephropathy. In addition, serum total cholesterol (TC) and low-density lipoprotein (LDL) levels in the blood were abnormally elevated, steatosis was observed in the liver cells, and atherosclerotic lesions were observed in the aortic vessels in ApoE/NOS3−/− adult mice. In conclusion, ApoE/NOS3−/− adult mice are a satisfactory model of hypertension and atherosclerosis and can be utilized for studies on cardiovascular diseases.
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Van Eck, Miranda, Nicole Herijgers, Ko Willems Van Dijk, Louis M. Havekes, Marten H. Hofker, Pieter H. E. Groot, and Theo J. C. Van Berkel. "Effect of Macrophage-Derived Mouse ApoE, Human ApoE3-Leiden, and Human ApoE2 (Arg158→Cys) on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice." Arteriosclerosis, Thrombosis, and Vascular Biology 20, no. 1 (January 2000): 119–27. http://dx.doi.org/10.1161/01.atv.20.1.119.
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Dory, L. "Post-transcriptional regulation of apolipoprotein E expression in mouse macrophages by phorbol ester." Biochemical Journal 292, no. 1 (May 15, 1993): 105–11. http://dx.doi.org/10.1042/bj2920105.
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Phorbol ester-mediated differentiation of THP-1 cells (a human monocytic cell line) into mature macrophages is associated with a transcriptional induction of apolipoprotein E (apoE) expression [Auwerx, Deeb, Brunzell, Peng and Chait (1988) Biochemistry 27, 2651-2655]. Endotoxin, on the other hand, which may also act through activation of protein kinase C, is a potent inhibitor of apoE expression in mouse macrophages [Werb and Chin (1983) J. Biol. Chem. 258, 10642-10648]. The present experiments examine the effect of phorbol ester, an activator of protein kinase C, on the apoE expression in mouse thioglycollate-elicited peritoneal macrophages. Phorbol ester inhibits apoE expression in a specific, time- and dose-dependent manner. A 75% inhibition in the rate of apoE secretion, but not that of total protein, was observed following a 4.5 h incubation with 160 nM phorbol ester, although nearly full inhibition was obtained with 40 nM. The changes in apoE secretion were paralleled by similar changes in apoE synthesis, indicating synthesis as the primary site of action. The decreased rates of apoE synthesis are shown not to be due to increased apoE degradation. The profound inhibition of apoE synthesis was not accompanied by significant changes in apoE mRNA levels at any concentration of phorbol ester (up to 16 microM), or length of treatment (up to 24 h), suggesting a post-transcriptional locus of regulation of apoE expression. Although the early changes in apoE synthesis correlate with increased microsomal protein kinase C activity, the suppression of apoE expression persists even during conditions of nearly complete (> 95%) loss of protein kinase C activity, suggesting that the direct or indirect effect of protein kinase C on apoE expression is mediated by a stable phosphorylated protein, or that the observed effects are mediated through a protein kinase C species that is not readily downregulated by phorbol esters. The presented studies clearly demonstrate the potential importance of the translational regulation of apoE expression through the protein kinase C signal transduction pathway.
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Wang, Xiaohui, Rongwen Li, Alex Zacharek, Julie Landschoot-Ward, Fengjie Wang, Kuan-Han Wu, Michael Chopp, Jieli Chen, and Xu Cui. "Administration of Downstream ApoE Attenuates the Adverse Effect of Brain ABCA1 Deficiency on Stroke." International Journal of Molecular Sciences 19, no. 11 (October 28, 2018): 3368. http://dx.doi.org/10.3390/ijms19113368.
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The ATP-binding cassette transporter member A1 (ABCA1) and apolipoprotein E (ApoE) are major cholesterol transporters that play important roles in cholesterol homeostasis in the brain. Previous research demonstrated that specific deletion of brain-ABCA1 (ABCA1−B/−B) reduced brain grey matter (GM) and white matter (WM) density in the ischemic brain and decreased functional outcomes after stroke. However, the downstream molecular mechanism underlying brain ABCA1-deficiency-induced deficits after stroke is not fully understood. Adult male ABCA1−B/−B and ABCA1-floxed control mice were subjected to distal middle-cerebral artery occlusion and were intraventricularly infused with artificial mouse cerebrospinal fluid as vehicle control or recombinant human ApoE2 into the ischemic brain starting 24 h after stroke for 14 days. The ApoE/apolipoprotein E receptor 2 (ApoER2)/high-density lipoprotein (HDL) levels and GM/WM remodeling and functional outcome were measured. Although ApoE2 increased brain ApoE/HDL levels and GM/WM density, negligible functional improvement was observed in ABCA1-floxed-stroke mice. ApoE2-administered ABCA1−B/−B stroke mice exhibited elevated levels of brain ApoE/ApoER2/HDL, increased GM/WM density, and neurogenesis in both the ischemic ipsilateral and contralateral brain, as well as improved neurological function compared with the vehicle-control ABCA1−B/−B stroke mice 14 days after stroke. Ischemic lesion volume was not significantly different between the two groups. In vitro supplementation of ApoE2 into primary cortical neurons and primary oligodendrocyte-progenitor cells (OPCs) significantly increased ApoER2 expression and enhanced cholesterol uptake. ApoE2 promoted neurite outgrowth after oxygen-glucose deprivation and axonal outgrowth of neurons, and increased proliferation/survival of OPCs derived from ABCA1−B/−B mice. Our data indicate that administration of ApoE2 minimizes the adverse effects of ABCA1 deficiency after stroke, at least partially by promoting cholesterol traffic/redistribution and GM/WM remodeling via increasing the ApoE/HDL/ApoER2 signaling pathway.
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Sullivan, Patrick, Donald Schmechel, Christine Hulette, Ruby Ange, and Mark J. Alberts. "Apolipoprotein E Transgenic Mouse Model of Cerebral Amyloid Angiopathy." Stroke 32, suppl_1 (January 2001): 329. http://dx.doi.org/10.1161/str.32.suppl_1.329-c.
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76 Background: Cerebral amyloid angiopathy (CAA) is the second most common etiology for non-traumatic intracerebral hemorrhage (ICH). There is a significantly increased frequency of the apolipoprotein E (apoE) ε4 and ε2 alleles in patients with CAA and CAA-related ICH. This suggests a role for apoE in the pathogenesis of CAA and ICH. We have developed a unique transgenic mouse model using the human apoE gene to study the molecular mechanisms underlying CAA. Methods: The transgenic mouse model was created by gene targeting, which results in the expression of each human apoE isoform at physiologic levels in a correct spatial and temporal pattern. These mice do not contain any mutations in the amyloid precursor protein or cystatin C gene. Mice of all apoE genotypes were bred, and were matched for age and sex. Brains from aged mice were analyzed for gross ICH. Brain sections were stained with anti-mouse A-beta antibody (4G8) to detect vascular amyloid. Sections were also stained for blood using hematoxylin and eosin (H&E), and a Prussian Blue stain was used to detect iron and hemosiderin deposition. A thioflavin-S stain was used to determine if the vascular amyloid was fibrillar. Results: Brains from sacrificed aged (mean age=80 weeks) apoE transgenic mice showed positive staining for CAA in predominantly neocortical vessels. The apoE ε2/ε2 mice had the highest occurrence of CAA (70%, 7 of 10), followed by the ε4/ε4 mice (40%, 4 of 10). Only 10% (1 of 10) of the ε3/ε3 mice had CAA. Two aged mice homozygous for apoE ε4 had gross ICH at post-mortem inspection. Brain sections from these mice demonstrated red blood cell infiltration and iron/hemosiderin deposition in the brain parenchyma when examined by light microscopy. Conclusions: This human apoE transgenic mouse model provides a genetically well defined and environmentally controlled animal model for the study of CAA that closely resembles the condition found in humans. This model may be useful for the study of therapies for the prevention and treatment of CAA.
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Hiebert, Paul, Dan Wu, and David Granville. "Granzyme B contributes to impaired wound healing during chronic inflammation in apolipoprotein E knockout mice (P3036)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 114.19. http://dx.doi.org/10.4049/jimmunol.190.supp.114.19.
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Abstract Granzyme B (GzmB) is a serine protease expressed by immune cells during chronic inflammation and is capable of degrading extracellular matrix (ECM) proteins such as fibronectin (FN). Apolipoprotein E (ApoE) is a protein known to suppress inflammation and is expressed in skin. ApoE knockout (KO) mice develop an inflammatory skin phenotype when fed a high fat diet leading to impaired wound healing. We hypothesized that excessive GzmB activity contributes to impaired healing in ApoE KO mice through the degradation of ECM. Wild type (WT), ApoE KO and ApoE/GzmB double knockout (DKO) mice were fed a high fat diet for 30 weeks and given a 1 cm diameter skin wound on their mid dorsum. Wounds were allowed to heal for 16 days at which point the wounded tissue was harvested. All WT mouse wounds showed complete closure after 16 days while only 40% achieved closure in ApoE KO mice. Wound contraction was also slower in ApoE KO mice compared to WT controls (P<0.05). Histological analysis demonstrated persistent inflammation in ApoE KO mouse wounds at Day 16 featuring neutrophils, macrophages, T cells and GzmB. Wounded skin from ApoE KO mice also contained a FN fragment of similar size to that produced by GzmB in vitro. Compared to ApoE KO mice, DKO mice showed faster contraction (P<0.05) and better healing with 80% of wounds achieving closure by Day 16. These results suggest GzmB contributes to impaired wound healing in ApoE KO mouse wounds, possibly through excessive degradation of FN.
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Tai, Leon M., Kevin P. Koster, Jia Luo, Sue H. Lee, Yue-ting Wang, Nicole C. Collins, Manel Ben Aissa, Gregory R. J. Thatcher, and Mary Jo LaDu. "Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo." Journal of Biological Chemistry 289, no. 44 (September 12, 2014): 30538–55. http://dx.doi.org/10.1074/jbc.m114.600833.
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Previous data demonstrate that bexarotene (Bex), retinoid X receptor (RXR) agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer disease (AD)-transgenic mice either by increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. However, although the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If the APOE4 loss-of-function is lipidation of apoE4, then induction of ABCA1/ABCG1 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ) are highest in E4FAD hippocampus (HP) > E3FAD-HP > E4FAD cortex (CX) > E3FAD-CX, whereas levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6 months). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75–6 months) increased ABCA1, apoE4 lipoprotein-association/lipidation, and apoE4/Aβ complex, decreased soluble Aβ, and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG100268. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5–6 months) and actually increased soluble Aβ levels in E3FAD-CX and E4FAD-CX with the short-term protocol, possibly the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology, i.e. low levels of apoE4 lipoprotein association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.
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Wan, Wuzhou, Jean Lim, Michail Lionakis, Aymeric Rivollier, David McDermott, Brian Kelsall, Joshua Farber, and Philip Murphy. "Genetic deletion of chemokine receptor Ccr6 decreases atherogenesis in ApoE-deficient mice (117.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 117.2. http://dx.doi.org/10.4049/jimmunol.186.supp.117.2.
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Abstract Background—The chemokine receptor CCR6 and its ligand CCL20 are both expressed in human atheroma; however, their functional roles in atherogenesis remain undefined. Here, we addressed this question in the apolipoprotein E-deficient (ApoE-/-) mouse model of atherosclerosis. Methods and Results—Both Ccr6 and Ccl20 are expressed in atherosclerotic aorta from ApoE-/- mice. Atherosclerotic lesion area in the aorta in Ccr6-/-ApoE-/- mice was ~40% and ~30% smaller than in Ccr6+/+ApoE-/- mice at 16 and 24 weeks of age, respectively. In addition, lesions of Ccr6-/-ApoE-/- mice had 44% less macrophage content compared to Ccr6+/+ApoE-/- mice. Since monocytes are the source of lesional macrophages, we tested whether monocytes express Ccr6 and the effect of Ccr6 deletion on monocyte function. We found that Ccr6 was expressed on a subset of primary mouse monocytes and on the mouse monocyte/macrophage cell line RAW 264.7. The receptor was functional, as defined by Ccl20-induced chemotaxis of primary monocytes from wild type but not Ccr6-/- mice; moreover, Ccl20 induced monocytosis in ApoE-/- mice in vivo. Consistent with this, we observed 30% fewer monocytes in the circulating blood of Ccr6-/-ApoE-/- mice, mainly due to fewer CD11b+Ly6Chigh inflammatory monocytes. Conclusions—We conclude that Ccr6 promotes atherosclerosis in ApoE-deficient mice. This may be due in part to Ccr6 support of normal monocyte levels in blood in the model, as well as direct Ccr6-dependent monocyte migration.
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Roth, Lynn, Miche Rombouts, Dorien M. Schrijvers, Besa Emini Veseli, Wim Martinet, and Guido R. Y. De Meyer. "Acetylsalicylic Acid Reduces Passive Aortic Wall Stiffness and Cardiovascular Remodelling in a Mouse Model of Advanced Atherosclerosis." International Journal of Molecular Sciences 23, no. 1 (December 30, 2021): 404. http://dx.doi.org/10.3390/ijms23010404.
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Acetylsalicylic acid (ASA) is widely used in secondary prevention of cardiovascular (CV) disease, mainly because of its antithrombotic effects. Here, we investigated whether ASA can prevent the progression of vessel wall remodelling, atherosclerosis, and CV complications in apolipoprotein E deficient (ApoE−/−) mice, a model of stable atherosclerosis, and in ApoE−/− mice with a mutation in the fibrillin-1 gene (Fbn1C1039G+/−), which is a model of elastic fibre fragmentation, accompanied by exacerbated unstable atherosclerosis. Female ApoE−/− and ApoE−/−Fbn1C1039G+/− mice were fed a Western diet (WD). At 10 weeks of WD, the mice were randomly divided into four groups, receiving either ASA 5 mg/kg/day in the drinking water (ApoE−/− (n = 14), ApoE−/−Fbn1C1039G+/− (n = 19)) or plain drinking water (ApoE−/− (n = 15), ApoE−/−Fbn1C1039G+/− (n = 21)) for 15 weeks. ApoE−/−Fbn1C1039G+/− mice showed an increased neutrophil–lymphocyte ratio (NLR) compared to ApoE−/− mice, and this effect was normalised by ASA. In the proximal ascending aorta wall, ASA-treated ApoE−/−Fbn1C1039G+/− mice showed less p-SMAD2/3 positive nuclei, a lower collagen percentage and an increased elastin/collagen ratio, consistent with the values measured in ApoE−/− mice. ASA did not affect plaque progression, incidence of myocardial infarction and survival of ApoE−/−Fbn1C1039G+/− mice, but systolic blood pressure, cardiac fibrosis and hypertrophy were reduced. In conclusion, ASA normalises the NLR, passive wall stiffness and cardiac remodelling in ApoE−/−Fbn1C1039G+/− mice to levels observed in ApoE−/− mice, indicating additional therapeutic benefits of ASA beyond its classical use.
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Kim, Jungsu, Adam E. M. Eltorai, Hong Jiang, Fan Liao, Philip B. Verghese, Jaekwang Kim, Floy R. Stewart, Jacob M. Basak, and David M. Holtzman. "Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis." Journal of Experimental Medicine 209, no. 12 (November 5, 2012): 2149–56. http://dx.doi.org/10.1084/jem.20121274.
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The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
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Adingupu, Damilola D., Suvi E. Heinonen, Anne-Christine Andréasson, Mikael Brusberg, Andrea Ahnmark, Margareta Behrendt, Brendan Leighton, and Ann-Cathrine Jönsson-Rylander. "Hyperglycemia Induced by Glucokinase Deficiency Accelerates Atherosclerosis Development and Impairs Lesion Regression in Combined Heterozygous Glucokinase and the Apolipoprotein E-Knockout Mice." Journal of Diabetes Research 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/8630961.
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Aim. Models combining diabetes and atherosclerosis are important in evaluating the cardiovascular (CV) effects and safety of antidiabetes drugs in the development of treatments targeting CV complications. Our aim was to evaluate if crossing the heterozygous glucokinase knockout mouse (GK+/−) and hyperlipidemic mouse deficient in apolipoprotein E (ApoE−/−) will generate a disease model exhibiting a diabetic and macrovascular phenotype.Methods. The effects of defective glucokinase on the glucose metabolism and on the progression and regression of atherosclerosis on high-fat diets were studied in both genders of GK+/−ApoE−/−and ApoE−/−mice. Coronary vascular function of the female GK+/−ApoE−/−and ApoE−/−mice was also investigated.Results. GK+/−ApoE−/−mice show a stable hyperglycemia which was increased on Western diet. In oral glucose tolerance test, GK+/−ApoE−/−mice showed significant glucose intolerance and impaired glucose-stimulated insulin secretion. Plasma lipids were comparable with ApoE−/−mice; nevertheless the GK+/−ApoE−/−mice showed slightly increased atherosclerosis development.Conclusions. The GK+/−ApoE−/−mice showed a stable and reproducible hyperglycemia, accelerated atherosclerotic lesion progression, and no lesion regression after lipid lowering. This novel model provides a promising tool for drug discovery, enabling the evaluation of compound effects against both diabetic and cardiovascular endpoints simultaneously in one animal model.
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Li, Li, Rongwen Li, Alex Zacharek, Fengjie Wang, Julie Landschoot-Ward, Michael Chopp, Jieli Chen, and Xu Cui. "ABCA1/ApoE/HDL Signaling Pathway Facilitates Myelination and Oligodendrogenesis after Stroke." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4369. http://dx.doi.org/10.3390/ijms21124369.
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ATP-binding cassette transporter A1 (ABCA1) plays an important role in the regulation of apolipoprotein E (ApoE) and the biogenesis of high-density lipoprotein (HDL) cholesterol in the mammalian brain. Cholesterol is a major source for myelination. Here, we investigate whether ABCA1/ApoE/HDL contribute to myelin repair and oligodendrogenesis in the ischemic brain after stroke. Specific brain ABCA1-deficient (ABCA1-B/-B) and ABCA1-floxed (ABCA1fl/fl) control mice were subjected to permanent distal middle-cerebral-artery occlusion (dMCAo) and were intracerebrally administered (1) artificial mouse cerebrospinal fluid (CSF) as vehicle control, (2) human plasma HDL3, and (3) recombined human ApoE2 starting 24 h after dMCAo for 14 days. All stroke mice were sacrificed 21 days after dMCAo. The ABCA1-B/-B–dMCAo mice exhibit significantly reduced myelination and oligodendrogenesis in the ischemic brain as well as decreased functional outcome 21 days after stroke compared with ABCA1fl/fl mice; administration of human ApoE2 or HDL3 in the ischemic brain significantly attenuates the deficits in myelination and oligodendrogenesis in ABCA1-B/-B–dMCAo mice ( p < 0.05, n = 9/group). In vitro, ABCA1-B/-B reduces ApoE expression and decreases primary oligodendrocyte progenitor cell (OPC) migration and oligodendrocyte maturation; HDL3 and ApoE2 treatment significantly reverses ABCA1-B/-B-induced reduction in OPC migration and oligodendrocyte maturation. Our data indicate that the ABCA1/ApoE/HDL signaling pathway contributes to myelination and oligodendrogenesis in the ischemic brain after stroke.
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Nagarajan, Shanmugam. "Loss of Fcgamma receptors ameliorates initiation and progression of atherosclerosis in hyperlipidemic mouse model (94.24)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 94.24. http://dx.doi.org/10.4049/jimmunol.182.supp.94.24.
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Abstract OxLDL generated during hyperlipidemia is known to induce an autoimmune response resulting in the production of anti-oxLDL IgG. In humans and in the hyperlipidemic mouse model, the titer of autoantibodies against oxLDL correlates with the progression of atherosclerosis. Although the presence of anti-oxLDL IgG is well documented, the contribution of FcγRs to the initiation and/or progression of atherosclerosis has not been studied in detail. First, to address the presence of oxLDL-IC in atherosclerotic lesions, descending aorta from wild type (WT) and apoE-/- mice fed chow diet for 18 weeks and oxLDL-IC in the lysates were determined. OxLDL-IC was detected in the aortic lysates of both WT and apoE-/- mice. However, the levels were elevated about 8 fold in apoE-/- mice. The presence of anti-oxLDL IgG in atherosclerotic lesions in patients and animal models, suggests the possibility of oxLDL-IC deposition in the lesions. To determine the role of FcγRs in the initiation and/or progression of atherosclerosis, we have generated apoE-/-γ-chain-/- mice by mating γ-chain-/- mice with apoE-/- mice. ApoE-/- and apoE-/-γ-chain-/- mice (age 4 wk) were fed chow diet for 20 weeks. Plasma cholesterol levels were similar in apoE-/- and apoE-/-γ-chain-/- mice. Atherosclerotic lesions in aortic sinus were determined by staining cryosections with Oil Red O. Enface analysis of the descending aorta was performed by staining descending aorta from the aortic arch to the iliac bifurcation with Sudan IV. Both analyses showed about a 50% reduction in lesions in apoE-/-γ-chain-/- mice compared to apoE-/- mice. These novel findings suggest activating FcγRs contribute to the progression of atherosclerosis. (Supported by NIH HL086674).
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Glaros, Elias N., Woojin S. Kim, and Brett Garner. "Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition." Clinical Science 118, no. 12 (March 30, 2010): 727–36. http://dx.doi.org/10.1042/cs20090452.
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Sphingolipids including sphingomyelin have been implicated as potential atherogenic lipids. Studies in apoE (apolipoprotein E)-null mice have revealed that the serine palmitoyltransferase inhibitor myriocin reduces plasma levels of sphingomyelin, ceramide, sphingosine-1-phosphate and glycosphingolipids and that this is associated with potent inhibition of atherosclerosis. Interestingly, hepatic apoA-I (apolipoprotein A-I) synthesis and plasma HDL (high-density lipoprotein)-cholesterol levels were also increased in apoE-null mice treated with myriocin. Since myriocin is a known inhibitor of ERK (extracellular-signal-related kinase) phosphorylation, we assessed the possibility that myriocin may be acting to increase hepatic apoA-I production via this pathway. To address this, HepG2 cells and primary mouse hepatocytes were treated with 200 μM myriocin for up to 48 h. Myriocin increased apoA-I mRNA and protein levels by approx. 3- and 2-fold respectively. Myriocin also increased apoA-I secretion up to 3.5-fold and decreased ERK phosphorylation by approx. 70%. Similar findings were obtained when primary hepatocytes were isolated from apoE-null mice that were treated with myriocin (intraperitoneal injection at a dose of 0.3 mg/kg body weight). Further experiments revealed that the MEK (mitogen-activated protein kinase/ERK kinase) inhibitor PD98059 potently inhibited ERK phosphorylation, as expected, and increased primary hepatocyte apoA-I production by 3-fold. These results indicate that ERK phosphorylation plays a role in regulating hepatic apoA-I expression and suggest that the anti-atherogenic mechanism of action for myriocin may be linked to this pathway.
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Herzine, Ameziane, Ghita Sekkat, Sandra Kaminski, Gaetano Calcagno, Sandrine Boschi-Muller, Hela Safi, Catherine Corbier, Sophie Siest, Thomas Claudepierre, and Frances T. Yen. "Lipolysis-Stimulated Lipoprotein Receptor Acts as Sensor to Regulate ApoE Release in Astrocytes." International Journal of Molecular Sciences 23, no. 15 (August 3, 2022): 8630. http://dx.doi.org/10.3390/ijms23158630.
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Astroglia play an important role, providing de novo synthesized cholesterol to neurons in the form of ApoE-lipidated particles; disruption of this process can increase the risk of Alzheimer’s disease. We recently reported that glia-specific suppression of the lipolysis-stimulated lipoprotein receptor (LSR) gene leads to Alzheimer’s disease-like memory deficits. Since LSR is an Apo-E lipoprotein receptor, our objective of this study was to determine the effect of LSR expression modulation on cholesterol and ApoE output in mouse astrocytes expressing human ApoE3. qPCR analysis showed that siRNA-mediated lsr knockdown significantly increased expression of the genes involved in cholesterol synthesis, secretion, and metabolism. Analysis of media and lipoprotein fractions showed increased cholesterol and lipidated ApoE output in HDL-like particles. Further, lsr expression could be upregulated when astrocytes were incubated 5 days in media containing high levels (two-fold) of lipoprotein, or after 8 h treatment with 1 µM LXR agonist T0901317 in lipoprotein-deficient media. In both conditions of increased lsr expression, the ApoE output was repressed or unchanged despite increased abca1 mRNA levels and cholesterol production. We conclude that LSR acts as a sensor of lipoprotein content in the medium and repressor of ApoE release, while ABCA1 drives cholesterol efflux, thereby potentially affecting cholesterol load, ApoE lipidation, and limiting cholesterol trafficking towards the neuron.
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Brown, Matthew L., Katsumasa Yui, Jonathan D. Smith, Renée C. LeBoeuf, Wei Weng, Patrick K. Umeda, Ran Li, Ruiling Song, Sandra H. Gianturco, and William A. Bradley. "The murine macrophage apoB-48 receptor gene (Apob-48r)." Journal of Lipid Research 43, no. 8 (August 2002): 1181–91. http://dx.doi.org/10.1194/jlr.m100395-jlr200.
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Previously we cloned the human macrophage apolipoprotein B-48 receptor (ApoB-48R) and documented its expression in human atherosclerotic foam cells (1). Now we have identified and characterized the murine macrophage apob-48r cDNA gene sequence and its chromasomal location. The cDNA (3,615 bp) -deduced amino acid (aa) sequence (942 aa) is ∼45% identical to the human macrophage APOB-48R, but not to other known gene families. The murine Apob-48r gene, like the human APOB-48R gene, consists of four exons interrupted by three small introns and is syntenically located on chromosome 7. Functionally significant conserved domains include an N-terminal hydrophobic domain, a glycosaminoglycan attachment site, an N-glycosylation site, and an ExxxLL internalization motif C-terminal to the putative internal transmembrane domain. Two conserved coiled-coil domains are likely involved in the spontaneous homodimerization that generates the active dimeric ligand binding species (mouse, ∼190 kDa; human, ∼200 kDa). Transfection of the murine apoB-48R into Chinese hamster ovary cells (CHOs) confers apoB-48R function: rapid, high-affinity, specific uptake of known triglyceride-rich lipoprotein ligands of the apoB-48R and, of note, uptake of the cholesteryl ester-rich apoB-48-containing very low density lipoproteins that accumulate in atherosclerosis-prone apoE-deficient mice. Uptake of these ligands by murine apoB-48R-transfected CHOs causes saturable, visible cellular triglyceride and cholesterol accumulation in vitro that resemble foam cells of atherosclerotic lesions.In aggregate, the data presented here and that previously published suggest that the apoE-independent murine apoB-48R pathway may contribute to the spontaneous development of atherosclerotic lesions rich in macrophage-derived foam cells observed in apoE-deficient mice, a murine model of human atherosclerosis.
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Chen, Xiuping, Hanrui Zhang, Steve McAfee, and Cuihua Zhang. "The reciprocal relationship between adiponectin and LOX-1 in the regulation of endothelial dysfunction in ApoE knockout mice." American Journal of Physiology-Heart and Circulatory Physiology 299, no. 3 (September 2010): H605—H612. http://dx.doi.org/10.1152/ajpheart.01096.2009.
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We hypothesized that the reciprocal association between adiponectin and lectin-like oxidized LDL (ox-LDL) receptor (LOX)-1 contributes to the regulation of aortic endothelial dysfunction in atherosclerosis. To test this hypothesis, endothelium-dependent (ACh) and endothelium-independent (sodium nitroprusside) vasorelaxation of isolated aortic rings from control mice, apolipoprotein E (ApoE) knockout (KO) mice, and ApoE KO mice treated with either adiponectin (15 μg·day−1·mouse−1 sc for 8 days) or neutralizing antibody to LOX-1 (anti-LOX-1, 16 μg/ml, 0.1 ml/mouse ip for 7 days) were examined. Although vasorelaxation to sodium nitroprusside was not different between control and ApoE KO mice, relaxation to ACh was impaired in ApoE KO mice. Adiponectin and anti-LOX-1 restored nitric oxide-mediated endothelium-dependent vasorelaxation in ApoE KO mice. Aortic ROS formation and ox-LDL uptake were increased in ApoE KO mice. Both adiponectin and anti-LOX-1 treatment reduced ROS production and aortic ox-LDL uptake. In mouse coronary artery endothelial cells, TNF-α incubation increased endothelial LOX-1 expression. Adiponectin reduced TNF-α-induced LOX-1 expression. Consistently, in ApoE KO mice, adiponectin treatment reversed elevated LOX-1 expression in aortas. Immunofluorescence staining showed that adiponectin was mainly colocalized with endothelial cells. Although adiponectin expression was lower in ApoE KO versus control mice, anti-LOX-1 increased aortic adiponectin expression, suggesting a reciprocal regulation between adiponectin and LOX-1. Moreover, both adiponectin and anti-LOX-1 reduced NF-κB expression in ApoE KO mice. Thus, adiponectin and LOX-1 may converge on NF-κB signaling to regulate their function. In conclusion, our results indicate that the reciprocal regulation between adiponectin and LOX-1 amplifies oxidative stress and ox-LDL uptake, leading to endothelial dysfunction in atherosclerosis.
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Maloney, Bryan, Yuan-Wen Ge, George M. Alley, and Debomoy K. Lahiri. "Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer’s disease." Journal of Neurochemistry 103, no. 3 (November 2007): 1237–57. http://dx.doi.org/10.1111/j.1471-4159.2007.04831.x.
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Nagarajan, Shanmugam, Xinmei Zhu, Doug Feck, Bane Popovic, and Murugesan Velayutham. "Mouse Fcgamma Receptor IV dependent inflammatory cytokine and chemokine response contributes to progression of atherosclerosis in apoE hyperlipidemic mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 124.6. http://dx.doi.org/10.4049/jimmunol.196.supp.124.6.
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Abstract Fcgamma receptors (FcγRs) are classified as activating (FcγRI, III, and IV) and inhibitory (FcγRII) receptors. Others and we have demonstrated that combined deficiency of all the three activating FcγRs (I, III and IV) in apolipoprotein E (apoE)-Fcγ chain double knockout (dKO) mice decreased atherosclerosis. In this report, we investigated the independent role of FcγRI and FcγRIV in the progression of atherosclerosis. We tested the hypothesis that FcγRI and FcγRIV exacerbate atherosclerosis using apoE-FcγRI dKO and apoE-FcγRIV dKO mice. Our results show that arterial lesions were not different between apoE-FcγRI dKO and apoE knockout (apoE KO) mice. Interestingly, arterial lesions were significantly decreased in a regular chow or a high-fat diet fed apoE-FcγRIV dKO male and female mice, relative to apoE KO mice. Bone marrow chimeras were used to address the relative contribution of FcγRIV expressed on hematopoietic cells including macrophages and dendritic cell. ApoE KO mice transplanted with apoE-FcγRIV dKO marrow showed significantly reduced arterial lesions relative to recipient mice transplanted with apoE KO marrow. Next, we investigated whether pro-inflammatory response contributed to the pro-atherogenic effect of FcγRIV. Activated CD4+ T cells of apoE-FcγRIV dKO mice showed increased secretion of IL-10, whereas IFN-γ and IL-17 by T cells were decreased. Interestingly, dendritic cells at the lesion-prone vascular site from apoE-FcγRIV dKO mice induced increased IL-10 secretion by LDL-specific T cells. Collectively, our findings suggest that the pro-inflammatory responses initiated by FcγRIV, one of the activating FcγRs, contribute to the progression of atherosclerosis. Supported by NIH grant HL086674.
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Michel, Frédéric, Serge Simonet, Christine Vayssettes-Courchay, Florence Bertin, Patricia Sansilvestri-Morel, Fabienne Bernhardt, Jérôme Paysant, et al. "Altered TP receptor function in isolated, perfused kidneys of nondiabetic and diabetic ApoE-deficient mice." American Journal of Physiology-Renal Physiology 294, no. 1 (January 2008): F120—F129. http://dx.doi.org/10.1152/ajprenal.00111.2007.
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Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A2) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH2, and 8-iso-PGF2α, but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF2α were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.
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Adams, Lisa C., Julia Brangsch, Jan O. Kaufmann, Dilyana B. Mangarova, Jana Moeckel, Avan Kader, Rebecca Buchholz, et al. "Effect of Doxycycline on Survival in Abdominal Aortic Aneurysms in a Mouse Model." Contrast Media & Molecular Imaging 2021 (April 27, 2021): 1–9. http://dx.doi.org/10.1155/2021/9999847.
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Background. Currently, there is no reliable nonsurgical treatment for abdominal aortic aneurysm (AAA). This study, therefore, investigates if doxycycline reduces AAA growth and the number of rupture-related deaths in a murine ApoE−/− model of AAA and whether gadofosveset trisodium-based MRI differs between animals with and without doxycycline treatment. Methods. Nine ApoE−/− mice were implanted with osmotic minipumps continuously releasing angiotensin II and treated with doxycycline (30 mg/kg/d) in parallel. After four weeks, MRI was performed at 3T with a clinical dose of the albumin-binding probe gadofosveset (0.03 mmol/kg). Results were compared with previously published wild-type control animals and with previously studied ApoE−/− animals without doxycycline treatment. Differences in mortality were also investigated between these groups. Results. In a previous study, we found that approximately 25% of angiotensin II-infused ApoE−/− mice died, whereas in the present study, only one out of 9 angiotensin II-infused and doxycycline-treated ApoE−/− mice (11.1%) died within 4 weeks. Furthermore, doxycycline-treated ApoE−/− mice showed significantly lower contrast-to-noise (CNR) values ( p = 0.017 ) in MRI compared to ApoE−/− mice without doxycycline treatment. In vivo measurements of relative signal enhancement (CNR) correlated significantly with ex vivo measurements of albumin staining (R2 = 0.58). In addition, a strong visual colocalization of albumin-positive areas in the fluorescence albumin staining with gadolinium distribution in LA-ICP-MS was shown. However, no significant difference in aneurysm size was observed after doxycycline treatment. Conclusion. The present experimental in vivo study suggests that doxycycline treatment may reduce rupture-related deaths in AAA by slowing endothelial damage without reversing aneurysm growth.
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Arora, Shitij, Mohammad Husain, Dileep Kumar, Hitesh Patni, Shresh Pathak, Devi Mehrotra, Vivek Kathi Reddy, et al. "Human immunodeficiency virus downregulates podocyte apoE expression." American Journal of Physiology-Renal Physiology 297, no. 3 (September 2009): F653—F661. http://dx.doi.org/10.1152/ajprenal.90668.2008.
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Apolipoprotein E ( apoE) has been demonstrated to play an important role in providing protection against mesangial cell injury. In the present study, we evaluated the role of apoE and its associated downstream effects in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). Control ( n = 6) and age- and sex-matched HIV-1 transgenic mice (Tg26, n = 6) were evaluated for their renal cortical expression of apoE. Renal tissue from Tg26 mice not only showed decreased apoE expression but also displayed downregulation of perlecan mRNA expression. In in vitro studies, conditionally immortalized human podocytes (CIHPs) were transduced with either NL4-3HIV (an HIV-1 construct lacking gag and pol, used for the development of Tg26 mouse model; NL4-3/CIHP) or empty vector (EV/CIHP); NL4-3/CIHPs and EV/CIHPs were studied for apoE mRNA expression. NL4-3/CIHPs showed reduction in apoE expression compared with EV/CIHPs. To evaluate the role of HIV-1 genes in the modulation of apoE expression, conditionally immortalized mouse podocytes (CIMPs) were transduced with individual HIV-1 gene constructs. Only nef-transduced CIMPs showed a decrease in apoE expression. To confirm this effect of nef in CIHPs, microarray analysis was performed in stable colonies of nef/CIHPs and EV/CIHPs. nef/CIHPs showed a 60% decrease in apoE and a 90% reduction in heparan sulfate mRNA expression. Moreover, nef transgenic mice showed a decrease in renal tissue expression of both apoE and perlecan. Both Tg26 and nef transgenic mice also showed areas of mesangial cell proliferation. These findings suggest that HIV-1-induced reduction in podocyte apoE expression and associated downregulation of podocyte perlecan might be contributing to mesangial cell (MC) phenotype in HIVAN.
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Khan, Naazneen, Yelena Alimova, Sophie J. Clark, Hemendra J. Vekaria, Adeline E. Walsh, Holden C. Williams, Gregory S. Hawk, Patrick G. Sullivan, Lance A. Johnson, and Timothy S. McClintock. "Human APOE ɛ3 and APOE ɛ4 Alleles Have Differential Effects on Mouse Olfactory Epithelium." Journal of Alzheimer's Disease 85, no. 4 (February 15, 2022): 1481–94. http://dx.doi.org/10.3233/jad-215152.
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Background: Alzheimer’s disease (AD) is a progressive age-dependent disorder whose risk is affected by genetic factors. Better models for investigating early effects of risk factors such as apolipoprotein E (APOE) genotype are needed. Objective: To determine whether APOE genotype produces neuropathologies in an AD-susceptible neural system, we compared effects of human APOE ɛ3 (E3) and APOE ɛ4 (E4) alleles on the mouse olfactory epithelium. Methods: RNA-Seq using the STAR aligner and DESeq2, immunohistochemistry for activated caspase-3 and phosphorylated histone H3, glucose uptake after oral gavage of 2-[1,2-3H (N)]-deoxy-D-glucose, and Seahorse Mito Stress tests on dissociated olfactory mucosal cells. Results: E3 and E4 olfactory mucosae show 121 differentially abundant mRNAs at age 6 months. These do not indicate differences in cell type proportions, but effects on 17 odorant receptor mRNAs suggest small differences in tissue development. Ten oxidoreductases mRNAs important for cellular metabolism and mitochondria are less abundant in E4 olfactory mucosae but this does not translate into differences in cellular respiration. E4 olfactory mucosae show lower glucose uptake, characteristic of AD susceptibility and consistent with greater expression of the glucose-sensitive gene, Asns. Olfactory sensory neuron apoptosis is unaffected at age 6 months but is greater in E4 mice at 10 months. Conclusion: Effects of human APOE alleles on mouse olfactory epithelium phenotype are apparent in early adulthood, and neuronal loss begins to increase by middle age (10 months). The olfactory epithelium is an appropriate model for the ability of human APOE alleles to modulate age-dependent effects associated with the progression of AD.
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Eitzman, Daniel T., Randal J. Westrick, Zuojun Xu, Julia Tyson, and David Ginsburg. "Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery." Blood 96, no. 13 (December 15, 2000): 4212–15. http://dx.doi.org/10.1182/blood.v96.13.4212.
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Abstract Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.
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Eitzman, Daniel T., Randal J. Westrick, Zuojun Xu, Julia Tyson, and David Ginsburg. "Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery." Blood 96, no. 13 (December 15, 2000): 4212–15. http://dx.doi.org/10.1182/blood.v96.13.4212.h8004212_4212_4215.
Full textAbstract:
Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.
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Kemal, Shahrnaz, and Robert Vassar. "Death by microglia." Journal of Experimental Medicine 216, no. 11 (October 23, 2019): 2451–52. http://dx.doi.org/10.1084/jem.20191536.
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The roles of microglia and ApoE in tauopathies, such as Alzheimer’s disease, remain elusive. In this issue, Shi et al. (https://doi.org/10.1084/jem.20190980) demonstrate that microglia-mediated innate immunity collaborates with ApoE to drive neurodegeneration and disease progression in a mouse model of tauopathy.