Astrocytes and Microglia Respond to Estrogen with Increased apoE mRNAin Vivoandin Vitro

doi:10.1006/exnr.1996.6360

Experimental Neurology

Volume 143, Issue 2, February 1997, Pages 313-318

https://doi.org/10.1006/exnr.1996.6360 Get rights and content

Abstract

This study examined the regulation of apolipoprotein E (apoE) by 17β-estradiol (E2) in brain glia, using rats with regular ovulatory cycles as anin vivomodel and cultured astrocytes and mixed glia asin vitromodels. Two brain regions were examined which had demonstrated transient synaptic remodeling during the estrous cycle. In the hippocampal CA1 region and the hypothalamic arcuate nucleus, apoE mRNA was elevated at proestrus when plasma E2 was high and synaptic density was increasing. Both astrocytes and microglia contributed to this increase in apoE mRNA.In vitro,E2 treatment had no effect on apoE mRNA levels in monotypic cultures of either astrocytes or microglia. In contrast, mixed glial cultures responded to E2 with increased apoE mRNA and protein, suggesting that heterotypic cellular interactions are important in the brain response to estrogens.In situhybridization in combination with cell-specific markers showed that E2 increased apoE mRNA levels in both astrocytes and microglia. These results, which are the first evidence of apoE mRNA localization to microgliain vivoand the control of apoE expression in brain cells by estrogens, are discussed in terms of the possible protective role of E2 in Alzheimer's disease and prior findings that emphasize the expression of apoE mRNA in astrocytes within the brain.

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Effects of DHA (omega-3 fatty acid) and estradiol on amyloid β-peptide regulation in the brain
2024, Brain Research
In the early stages of sporadic Alzheimer’s disease (SAD), there is a strong correlation between memory impairment and cortical levels of soluble amyloid-β peptide oligomers (Aβ). It has become clear that Aβ disrupt glutamatergic synaptic function, which can in turn lead to the characteristic cognitive deficits of SAD, but the actual pathways are still not well understood. This opinion article describes the pathogenic mechanisms underlying cerebral amyloidosis. These mechanisms are dependent on the amyloid precursor protein and concern the synthesis of Aβ peptides with competition between the non-amyloidogenic pathway and the amyloidogenic pathway (i.e. a competition between the ADAM10 and BACE1 enzymes), on the one hand, and the various processes of Aβ residue clearance, on the other hand. This clearance mobilizes both endopeptidases (NEP, and IDE) and removal transporters across the blood–brain barrier (LRP1, ABCB1, and RAGE). Lipidated ApoE also plays a major role in all processes. The disturbance of these pathways induces an accumulation of Aβ. The description of the mechanisms reveals two key molecules in particular: (i) free estradiol, which has genomic and non-genomic action, and (ii) free DHA as a preferential ligand of PPARα-RXRα and PPARɣ-RXRα heterodimers. DHA and free estradiol are also self-regulating, and act in synergy. When a certain level of chronic DHA and free estradiol deficiency is reached, a permanent imbalance is established in the central nervous system. The consequences of these deficits are revealed in particular by the presence of Aβ peptide deposits, as well as other markers of the etiology of SAD.
Current state of RNA delivery using lipid nanoparticles to extrahepatic tissues: A review towards clinical translation
2023, International Journal of Biological Macromolecules
Genetic medicine, including ribonucleic acid (RNA) therapy, has delivered numerous progresses to the treatment of diseases thanks to the development of lipid nanoparticles (LNPs) as a delivery vehicle. However, RNA therapeutics are still limited by the lack of safe, precise, and efficient delivery outside of the liver. Thus, to fully realize the potential of genetic medicine, strategies to arm LNPs with extrahepatic targeting capabilities are urgently needed. This review explores the current state of next-generation LNPs that can bring RNA biomolecules to their targeted organ. The main approaches commonly used are described, including the modulation of internal lipid chemistries, the use of conjugated targeting moieties, and the designs of clinical administration. This work will demonstrate the advances in each approach and the remaining challenges in the field, focusing on clinical translation.
Sporadic Alzheimer’s triad: Age, sex, and ApoE
2021, Assessments, Treatments and Modeling in Aging and Neurological Disease: The Neuroscience of Aging
Sporadic Alzheimer’s disease (sAD) has a multifactorial etiology, with age, sex, and the apolipoprotein E (ApoE) genotype established as the top three risk factors. sAD affects men and women differently in many aspects. Women have a higher risk of developing sAD and represent approximately 68% of all sAD cases. In addition, sex has been indicated to modulate the risk impact of genetic factors in the development of sAD and the patient response to sAD treatment. This chapter reviews both clinical and preclinical evidence on the interaction between sex and ApoE genetic polymorphism in the pathophysiology of sAD as well as the influence of the ApoE genotype on the treatment effects of estrogen-containing hormone replacement therapy (HRT). Findings from the majority of the studies indicate that the ε4 allele of the ApoE gene, the most potent genetic risk for sAD, confers a greater negative impact on women than on men. However, the question of which ApoE genotype can benefit from HRT remains to be elucidated. Further clarification of age–sex–ApoE interactions and understanding of the underlying mechanisms have important implications for population-targeted approaches for improved sAD diagnosis and intervention.
Tibolone attenuates inflammatory response by palmitic acid and preserves mitochondrial membrane potential in astrocytic cells through estrogen receptor beta
2019, Molecular and Cellular Endocrinology
Palmitic acid (PA) induces several metabolic and molecular changes in astrocytes, and, it is involved in pathological conditions related to neurodegenerative diseases. Previously, we demonstrated that tibolone, a synthetic steroid with estrogenic, progestogenic and androgenic actions, protects cells from mitochondrial damage and morphological changes induced by PA. Here, we have evaluated which estrogen receptor is involved in protective actions of tibolone and analyzed whether tibolone reverses gene expression changes induced by PA. Tibolone actions on astrocytic cells were mimicked by agonists of estrogen receptor α (ERα) and β (ERβ), but the blockade of both ERs suggested a predominance of ERβ on mitochondria membrane potential. Expression analysis showed a significant effect of tibolone on genes associated with inflammation such as IL6, IL1B and miR155-3p. It is noteworthy that tibolone attenuated the increased expression of TERT, TERC and DNMT3B genes induced by palmitic acid. Our results suggest that tibolone has anti-inflammatory effects and can modulate pathways associated with DNA methylation and telomeric complex. However, future studies are needed to elucidate the role of epigenetic mechanisms and telomere-associated proteins on tibolone actions.
A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward
2019, Neuron
Alzheimer’s disease (AD) is considered a polygenic disorder. This view is clouded, however, by lingering uncertainty over how to treat the quasi “monogenic” role of apolipoprotein E (APOE). The APOE4 allele is not only the strongest genetic risk factor for AD, it also affects risk for cardiovascular disease, stroke, and other neurodegenerative disorders. This review, based mostly on data from human studies, ranges across a variety of APOE-related pathologies, touching on evolutionary genetics and risk mitigation by ethnicity and sex. The authors also address one of the most fundamental question pertaining to APOE4 and AD: does APOE4 increase AD risk via a loss or gain of function? The answer will be of the utmost importance in guiding future research in AD.
Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors
2016, Frontiers in Neuroendocrinology
Alzheimer’s disease (AD) is an age-related neurodegenerative disorder for which there are no effective strategies to prevent or slow its progression. Because AD is multifactorial, recent research has focused on understanding interactions among the numerous risk factors and mechanisms underlying the disease. One mechanism through which several risk factors may be acting is inflammation. AD is characterized by chronic inflammation that is observed before clinical onset of dementia. Several genetic and environmental risk factors for AD increase inflammation, including apolipoprotein E4, obesity, and air pollution. Additionally, sex steroid hormones appear to contribute to AD risk, with age-related losses of estrogens in women and androgens in men associated with increased risk. Importantly, sex steroid hormones have anti-inflammatory actions and can interact with several other AD risk factors. This review examines the individual and interactive roles of inflammation and sex steroid hormones in AD, as well as their relationships with the AD risk factors apolipoprotein E4, obesity, and air pollution.

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^☆: E. Knobil, Eds.J. D. Neill, Eds.

¹: Both authors contributed equally and share first authorship.

²: To whom correspondence and reprint requests should be addressed. Fax: (213) 740-0853.

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Experimental Neurology

Abstract

References (28)

Association of apolipoprotein E genotype with brain levels of apolipoprotein E and apolipoprotein J (clusterin) in Alzheimer's disease

Mol. Brain Res.

Estrogen-induced increase in the uptake of cholesterol-rich very low density lipoproteins in perfused rabbit liver

Metabolism

Metabolic regulation of plasma apolipoprotein E by estrogen and progesterone in the baboon (Papio

Metabolism

Clusterin expression by astrocytes is influenced by transforming growth factor β1 and heterotypic cell interactions

J. Neuroimmunol.

Expression of apolipoprotein E mRNA in rat microglia

Neurosci. Lett.

Synaptic remodeling in the rat arcuate nucleus during the estrous cycle

Neuroscience

Apolipoprotein E polymorphism and Alzheimer's disease

Lancet

Cloning of hippocampal poly(A) RNA sequences that increase after entorhinal cortex lesion in adult rat

Mol. Brain Res.

Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning

Mol. Brain Res.

Microglia in the neurohypophysis associate with and endocytose terminal portions of neurosecretory neurons

Neuroscience

ApoE immunoreactivity and microglial cells in Alzheimer's disease brain

Neurosci. Lett.

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science

The neuroendocrine control of the ovarian cycle of the rat

The Physiology of Reproduction

Cited by (227)

Effects of DHA (omega-3 fatty acid) and estradiol on amyloid β-peptide regulation in the brain

Current state of RNA delivery using lipid nanoparticles to extrahepatic tissues: A review towards clinical translation

Sporadic Alzheimer’s triad: Age, sex, and ApoE

Tibolone attenuates inflammatory response by palmitic acid and preserves mitochondrial membrane potential in astrocytic cells through estrogen receptor beta

A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward

Interactions between inflammation, sex steroids, and Alzheimer's disease risk factors

Brief CommunicationAstrocytes and Microglia Respond to Estrogen with Increased apoE mRNAin Vivoandin Vitro☆

Abstract

Mol. Brain Res.

Metabolism

Metabolism

J. Neuroimmunol.

Neurosci. Lett.

Neuroscience

Lancet

Mol. Brain Res.

Mol. Brain Res.

Neuroscience

Neurosci. Lett.

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Science

The neuroendocrine control of the ovarian cycle of the rat

The Physiology of Reproduction

Brief Communication
Astrocytes and Microglia Respond to Estrogen with Increased apoE mRNAin Vivoandin Vitro☆