Estrogen, Astrocyte Reactivity, and Sex Differences in Alzheimer's Disease
阿尔茨海默病中的雌激素、星形胶质细胞反应性和性别差异
基本信息
- 批准号:10662993
- 负责人:
- 金额:$ 194.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAccelerationAgeAge MonthsAgonistAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmericanAndrogensAnimalsAromataseAstrocytesAutopsyBehavioralBindingBiochemicalBioinformaticsBiologicalBrainCell SeparationChIP-seqChromatinClinicalCognitionCognitiveDataData SetDependovirusDevelopmentEpigenetic ProcessEstradiolEstrogen Receptor alphaEstrogen ReceptorsEstrogen deficiencyEstrogensExhibitsFemaleGene ExpressionGenesGenomicsGlial Fibrillary Acidic ProteinGonadal structureHippocampusHormonesHumanImmunofluorescence ImmunologicImpairmentKnock-outKnowledge PortalLabelLinkLoxP-flanked alleleMagnetismMeasuresMediatingMedical RecordsMemoryMemory LossMemory impairmentMicroinjectionsModelingMolecularMorphologyMusNerve DegenerationNeuronsOutcomePathway interactionsPerimenopausePhenotypePostmenopausePrevention strategyProductionProteinsRecordsReportingResearchRiskRoleSeveritiesSex DifferencesSignal TransductionSmall Interfering RNASynapsesTestingTissuesTransgenic OrganismsWestern BlottingWomanage relatedagedanalogclinically relevantconditional knockoutenzyme activitygenome-wide analysishuman dataknock-downmalemenmouse modelneuron lossneuropathologyneuroprotectionneurotoxicitynew therapeutic targetnovelnovel therapeutic interventionolder womenpharmacologicpreventpromotersexsingle nucleus RNA-sequencingsynaptogenesistheoriestranscriptometranscriptome sequencing
项目摘要
SUMMARY
Nearly two-thirds of the more than 6 million Americans living with Alzheimer’s disease (AD) are women; however,
the molecular mechanisms underlying this sex difference in AD vulnerability are largely unknown. Prior research
has reported lower levels of estrogen in the brain of women with AD. The long-term objective of this application
is to define the role of estrogen deficiency in the observed sex-specific difference in AD vulnerability. Aromatase,
which converts androgens to estrogens, is mainly expressed in the brain and gonads of mice. We demonstrated
that knockout of aromatase locally in the mouse brain (bArKO) or totally in whole body (tArKO) causes sex-
specific memory deficits in old female mice. This phenotype is more severe in tArKO mice with estrogen
deficiency throughout the body vs. bArKO mice with estrogen deficiency only in the brain. Estrogen exerts its
biological action via binding to estrogen receptors (ERs). Treatment with the selective ERα agonist
propylpyrazoletriol rescued memory loss in female tArKO mice. Old female tArKO, but not old male tArKO mice,
exhibited fewer neurons in the hippocampus compared to wild-type littermates. RNA-seq, qPCR, and
immunofluorescence analyses of the hippocampus from young or old bArKO mice of both sexes revealed
astrocyte reactivity and related gene expression and morphologic changes only in old female bArKO mice. These
data suggested a novel mechanism in which estrogen deficiency leads to astrocyte reactivity. We hypothesize
that deficiency of estrogen/ERα signaling in the brain after menopause causes sex-specific astrocyte reactivity,
resulting in AD-related neuropathology and memory loss, leading to increased AD vulnerability in females. To
ascertain the mechanisms connecting estrogen deficiency in the brain to sex differences in AD vulnerability, we
propose the following aims: 1. Determine whether reversal of aromatase deletion and estrogen deficiency
reduces astrocyte reactivity and protects against neurodegeneration and memory loss. We will use transgenic
and pharmacological approaches to restore brain aromatase expression or estrogen action in bArKO and tArKO
mice at different ages. The estrogen/ERα-mediated genomic mechanisms responsible for the suppression of
sex-specific hippocampal astrocyte reactivity, neurodegeneration, and memory loss will be determined using
integrative genome-wide analyses employing single-nucleus (sn) RNA-seq, ERα-ChIP-seq, and snATAC-seq on
freshly isolated hippocampal astrocytes. 2. Determine whether conditional knockout of ERα in hippocampal
astrocytes of APPNL-G-F mice accelerates astrocyte reactivity, memory loss, and AD-related neuropathology. In
parallel, we will assess estrogen levels, expression of aromatase and ERα, and sex-specific expression of
reactive astrocyte-related genes in existing human datasets and postmortem hippocampal tissues and their
correlation with the severity of AD pathology and memory deficits in medical records of women and age-matched
men with AD. We expect that the findings from the proposed studies will identify new drug targets and lead to
novel therapeutical strategies for the prevention and treatment of AD.
摘要
在600多万患有阿尔茨海默病(AD)的美国人中,近三分之二是女性;然而,
阿尔茨海默病易感性的性别差异背后的分子机制很大程度上是未知的。前期研究
据报道,患有阿尔茨海默病的女性大脑中雌激素水平较低。此应用程序的长期目标是
目的是确定雌激素缺乏在观察到的AD易感性性别差异中的作用。芳香酶,
它将雄激素转化为雌激素,主要在小鼠的大脑和性腺中表达。我们演示了
小鼠大脑局部(Barko)或全身(Tarko)芳香酶的敲除会导致性行为--
老年雌性小鼠的特异性记忆缺陷。这种表型在服用雌激素的Tarko小鼠中更为严重。
全身缺乏症与只有大脑雌激素缺乏症的Barko小鼠。雌激素发挥其作用
通过与雌激素受体(ER)结合发挥生物学作用。选择性ER-α激动剂的治疗
丙基吡唑三醇挽救雌性Tarko小鼠的记忆丧失。年迈的雌性塔尔科老鼠,但不是年老的雄性塔尔科老鼠,
与野生型乳鼠相比,海马区的神经元较少。RNA-seq、qPCR和
免疫荧光分析显示,年轻或老年雄性Barko小鼠的海马区
星形胶质细胞反应性及相关基因表达和形态变化仅见于老年雌性Barko小鼠。这些
数据表明,雌激素缺乏导致星形胶质细胞反应的新机制。我们假设
绝经后大脑中雌激素/ERα信号的缺失会导致性别特异性星形胶质细胞的反应,
导致与AD相关的神经病理和记忆丧失,导致女性AD易感性增加。至
确定大脑中雌激素缺乏与AD易感性的性别差异有关的机制
提出以下目标:1.确定芳香酶缺失和雌激素缺乏的逆转
降低星形胶质细胞的反应性,防止神经退化和记忆力丧失。我们将使用转基因技术
以及恢复Barko和Tarko脑芳香酶表达或雌激素作用的药理学方法
不同年龄的小鼠。雌激素/内质网α介导的基因组机制抑制卵巢癌细胞增殖
性别特异性的海马星形胶质细胞反应性、神经退行性变和记忆丧失将通过
使用单核(SN)rna-seq、ERα-chIP-seq和Snatac-seq的全基因组综合分析
新鲜分离的海马区星形胶质细胞。2.确定海马区ERα是否存在条件性敲除
APPNL-G-F小鼠的星形胶质细胞加速星形胶质细胞的反应、记忆丧失和AD相关的神经病理。在……里面
同时,我们将评估雌激素水平,芳香酶和ERα的表达,以及性别特异性表达
现有人类数据集和死后海马组织中的反应性星形胶质细胞相关基因及其意义
女性及年龄匹配患者病历与AD病理严重程度及记忆障碍的相关性
阿尔茨海默病患者。我们预计,拟议研究的结果将确定新的药物靶点,并导致
防治阿尔茨海默病的新治疗策略。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Serdar E. Bulun其他文献
グラビア・目で見る遺伝子異常と婦人科内分泌疾患―早発卵巣不全―
凹印/可见基因异常与妇科内分泌疾病 - 卵巢早衰 -
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Masanori Ono;Tetsuo Maruyama;Mamoru Tanaka;Daisuke Aoki;Serdar E. Bulun;河村和弘・佐藤可野・鈴木直 - 通讯作者:
河村和弘・佐藤可野・鈴木直
STEROYL-CoA DESATURASE INHIBITION IS ASSOCIATED WITH DECREASED UTERINE LEIOMYOMA CELL VIABILITY
- DOI:
10.1016/j.fertnstert.2023.08.600 - 发表时间:
2023-10-01 - 期刊:
- 影响因子:
- 作者:
Allison S. Komorowski;Azna Zuberi;John S. Coon V;Melania Anton;Serdar E. Bulun;Ping Yin - 通讯作者:
Ping Yin
Therapeutic targeting of the tryptophan-kynurenine-aryl hydrocarbon receptor pathway with apigenin in MED12-mutant leiomyoma cells
芹菜素对 MED12 突变型平滑肌瘤细胞中色氨酸-犬尿氨酸-芳烃受体通路的治疗靶向作用
- DOI:
10.1038/s41417-025-00881-0 - 发表时间:
2025-03-01 - 期刊:
- 影响因子:5.000
- 作者:
Takashi Iizuka;Azna Zuberi;Helen Wei;John S. Coon V;Melania Lidia Anton;Kadir Buyukcelebi;Mazhar Adli;Serdar E. Bulun;Ping Yin - 通讯作者:
Ping Yin
Role of WNT/CTNNB1 pathway in differentiation of human induced pluced pluripotent stem cells to endometrial stroma-like cells
WNT/CTNNB1通路在人诱导多能干细胞向子宫内膜基质样细胞分化中的作用
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Kaoru Miyazaki;Matthew T. Dyson;John S. Coon;Tetsuo Maruyama;Serdar E. Bulun - 通讯作者:
Serdar E. Bulun
Transcriptome analysis of endometrial stroma-like ofganoids differentiated from human induced pluripotent stem cells
人诱导多能干细胞分化的子宫内膜基质样细胞的转录组分析
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Kaoru Miyazaki ;Matthew T. Dyson ;John S. Coon;Maruyama T;Serdar E. Bulun - 通讯作者:
Serdar E. Bulun
Serdar E. Bulun的其他文献
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{{ truncateString('Serdar E. Bulun', 18)}}的其他基金
Environmental Pollutants and AHR pathway in Uterine Leiomyoma
环境污染物与子宫平滑肌瘤的 AHR 通路
- 批准号:
10567192 - 财政年份:2022
- 资助金额:
$ 194.24万 - 项目类别:
Epigenome, MED12 and Progesterone Action in Uterine Leiomyomas
表观基因组、MED12 和孕酮在子宫平滑肌瘤中的作用
- 批准号:
10396486 - 财政年份:2019
- 资助金额:
$ 194.24万 - 项目类别:
Epigenome, MED12 and Progesterone Action in Uterine Leiomyomas
表观基因组、MED12 和孕酮在子宫平滑肌瘤中的作用
- 批准号:
10153842 - 财政年份:2019
- 资助金额:
$ 194.24万 - 项目类别:
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