Hormonal modulators of glial ABCA1 and apoE levels

Fan, Jianjia; Shimizu, Yoko; Chan, Jeniffer; Wilkinson, Anna; Ito, Ayaka; Tontonoz, Peter; Dullaghan, Edie; Galea, Liisa A.M.; Pfeifer, Tom; Wellington, Cheryl L.

doi:10.1194/jlr.m042473

Cited by 15 publications

(12 citation statements)

References 74 publications

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“…Importantly, AZ7235 is neither a direct LXR agonist nor indirectly stimulates LXR activity, distinguishing AZ7235 from other compounds returned from our previous efforts that identified several compound classes that robustly stimulate both apoE and ABCA1 expression in astrocytes via the LXR-mediated pathway [39,46,47]. A recent study identified Ondansetron, an FDA-approved 5-HT3 antagonist, as an apoE modulator that also involves the LXR pathway [48].…”

Section: Discussionmentioning

confidence: 99%

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

et al. 2020

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Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL−/− CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXLdeficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.

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Section: Discussionmentioning

confidence: 99%

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

et al. 2020

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“…Estrogen has been shown to upregulate Apoe gene expression in C57Bl/6 mice by altering post‐transcriptional mechanisms via the recruitment of the Apoe mRNA to the translating pool of polysomes , within most mouse strains tested, including C57Bl/6 . Within an astrocytoma cell line, progesterone but not estrogen, was shown to induce APOE secretion , suggesting that cell‐type specific differences in response to hormones may dictate the APOE‐mediated control of HSPC function. Gender specific differences in APOE expression have been revealed within the context of Alzheimer's disease, in which the female gender and the ɛ4 genotype of APOE increases risk for Alzheimer's disease up to fourfold .…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation

et al. 2015

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Epigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated from DNMT3B7 transgenic embryos identified Apolipoprotein E (Apoe) as overexpressed. The CpG island controlling Apoe expression had lower levels of modified cytosines in DNMT3B7 transgenic HSPCs, corresponding with the observed increase in gene expression. Furthermore, we observed that spleens and bone marrows of female mice transplanted with DNMT3B7 transgenic HSPCs express very high levels of Apoe. Finally, the introduction of Apoe-overexpressing HSPCs into male recipients decreased bone marrow engraftment, recapitulating our original observations in female recipients. Our work reveals a dynamic interplay between the intrinsic epigenetic changes in HSPCs and extrinsic endocrine factors acting on these cells to regulate the efficiency of hematopoietic stem and progenitor cell engraftment and reconstitution. We have identified a novel mechanism by which gender-specific hormones modulate HSPC function, which could serve as a target for augmenting hematopoiesis in cases with limited HSC functionality.

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“…Immortalized astrocytes were derived from targeted replacement mice expressing human APOE alleles (kind gift from Dr. David Holtzman). These immortalized cell lines secrete human ApoE in HDL-like particles at equivalent levels to primary astrocytes from targeted replacement APOE knock-in mice and have been relied upon for studies of APOE ’s role in astrocyte metabolism by several groups 40–42 . Cells were maintained in Advanced DMEM (Gibco) supplemented with 1mM sodium pyruvate, 1X Geneticin, and 10% fetal bovine serum unless otherwise noted.…”

Section: Methodsmentioning

confidence: 99%

APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

Farmer

Williams

Devanney

et al. 2020

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Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimers disease, as well as in young cognitively normal carriers of the E4 allele of Apolipoprotein E, the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. Here, we undertook a multi-omic approach by combining single-cell RNA sequencing and stable isotope resolved metabolomics to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increases in lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggested an E4 associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the E4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing mice, young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a Warburg like endophenotype that is observable in young humans decades prior to clinically manifest AD.

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Hormonal modulators of glial ABCA1 and apoE levels

Cited by 15 publications

References 74 publications

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

Axl receptor tyrosine kinase is a regulator of apolipoprotein E

Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation

APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis

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