Role of Testosterone in Modulating Tau Pathogenesis in Females

睾酮在调节女性 Tau 发病机制中的作用

• 批准号: 10685501
• 负责人: Xu Chen
• 金额: $ 56.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685501
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Androgen Receptor; Androgens; Animals; Anti-Inflammatory Agents; Apolipoprotein E; Apolipoproteins; Astrocytes; Biology; Brain; Cerebrospinal Fluid; Clinical; Clinical Data; Cognitive deficits; Collaborations; Compensation; Data; Deposition; Development; Disease; Disease Pathway; Estrogens; Female; Functional disorder; Gene Expression; Genetic; Goals; Gonadal Steroid Hormones; Hormones; Human; Impaired cognition; Inflammation; Intervention; Knock-in; Knock-in Mouse; Knowledge; Link; Literature; Mediating; Metabolism; Microglia; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurons; Neurosecretory Systems; Operative Surgical Procedures; Outcome; Ovariectomy; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiological; Progesterone; Publishing; Receptor Signaling; Regulation; Reporting; Reproductive Biology; Research; Research Personnel; Risk Reduction; Role; Sex Differences; Signal Transduction; Stanolone; Supplementation; Synapses; Tauopathies; Testosterone; Therapeutic; Transgenic Mice; Translational Research; Woman; Work; brain cell; capsule; cell type; clinical application; cognitive function; conditional knockout; effective intervention; effective therapy; genetic manipulation; high risk; improved; insight; male; men; mouse model; neuroimaging; neuroinflammation; neuronal survival; neuroprotection; novel; pharmacologic; precision medicine; preclinical study; programs; protective effect; receptor-mediated signaling; reproductive senescence; response; sex; single nucleus RNA-sequencing; subcutaneous; tau Proteins; tau aggregation; tau-1; therapeutic target; transcriptome; transcriptomics

PROJECT SUMMARY Alzheimer’s disease (AD) and other tau-mediated neurodegenerative diseases are characterized by aggregation and spread of pathological tau protein in the brain. Despite decades of research, effective interventions to these diseases are still lacking. It is well-evidenced that women typically show greater tau pathology than men on the AD trajectory; yet the reason for such sex differences is poorly understood. A better understanding of the mechanisms underlying the greater tau deposition in women can benefit all by informing causal pathways of disease and therapeutic targets and strategies that are optimal for each sex. Clinical evidence suggests that low testosterone levels correlate with poorer cognitive function and greater risk for AD. In particular, a recent study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that women with lower testosterone tend to have higher levels of phosphorylated tau (p-tau) in cerebrospinal fluid (CSF), particularly among ApoE4 carriers. This suggest that lower testosterone levels that typically characterize women may predispose them to pathological tau, and contribute to sex differences observed in AD. To take these correlative findings to the necessary next step, our overall objectives are to establish the causal relationship between testosterone and tau in females, to explore the clinical applicability of testosterone therapy, and to elucidate the underlying molecular mechanisms. Given testosterone’s anti-inflammatory actions and neuroprotective effects on AD-related outcomes, we hypothesize that pharmacological induction of high testosterone protects against pathological tau accumulation and spread, diminishes neuroinflammation and ameliorates cognitive deficits associated with tau pathogenesis, particularly in ApoE4 females. Based on published preclinical studies on testosterone, we further hypothesize that the protective effects of testosterone are linked to androgen receptor signaling in astrocytes and neurons, leading to enhanced neuronal survival, synaptic integrity and reduces neuroinflammation. This project is a new direction in our research program: In collaboration with experts on reproductive biology and gene expression, we will combine our expertise in tau biology, sex hormones and transcriptomics to determine how testosterone modulates tau pathogenesis in a sex-specific manner. We will: 1) Determine how increase of testosterone levels affects tau pathogenesis in female tau transgenic mouse models with human ApoE4/E3 knock-in; 2) Elucidate the molecular mechanism underlying the protective effects of testosterone in ApoE4 females by single nucleus RNA sequencing, and determining the involvement of neuronal and astrocytic androgen receptor signaling. This project aims to close critical gaps in our understanding of mechanisms underlying sex differences in tau pathophysiology, and provide novel insights into the influence of androgen on molecular mechanisms central to AD pathogenesis. Results from the proposed research will address NIA strategic goals: understand the progression of Alzheimer’s (A), and identify potential therapeutic targets for the development of precision medicine treatments for men and women (D).

项目摘要 阿尔茨海默病（AD）和其他tau介导的神经退行性疾病的特征在于聚集 以及病理性tau蛋白在大脑中的扩散。尽管经过几十年的研究，有效的干预措施， 疾病仍然缺乏。有充分证据表明，女性通常比男性表现出更大的tau病理学， AD轨迹;然而，这种性别差异的原因知之甚少。更好地理解 女性中tau蛋白沉积更大的潜在机制可以通过告知以下因果途径而使所有人受益： 疾病和治疗目标和战略，是最佳的每一个性别。临床证据表明， 睾酮水平与认知功能较差和AD风险较高相关。特别是最近的一项研究， 阿尔茨海默氏病神经影像学倡议（ADNI）显示，睾丸激素水平较低的女性往往有 脑脊液（CSF）中磷酸化tau（p-tau）水平较高，特别是在ApoE 4携带者中。这 这表明，通常作为女性特征的较低睾酮水平可能使她们更容易患上病理性tau蛋白， 并有助于在AD中观察到的性别差异。为了把这些相关的发现带到必要的下一步， 我们的总体目标是建立女性睾酮和tau之间的因果关系，探索 睾酮治疗的临床适用性，并阐明潜在的分子机制。给定 睾酮的抗炎作用和神经保护作用对AD相关的结果，我们假设 高睾酮的药理学诱导防止病理性tau积累和扩散， 减少神经炎症并改善与tau发病机制相关的认知缺陷， ApoE 4女性基于已发表的睾酮临床前研究，我们进一步假设， 睾酮的保护作用与星形胶质细胞和神经元中的雄激素受体信号有关， 增强神经元存活、突触完整性并减少神经炎症。该项目是一个新的方向， 我们的研究计划：与生殖生物学和基因表达专家合作，我们将联合收割机 我们在tau生物学、性激素和转录组学方面的专业知识，以确定睾酮如何调节tau 发病机制以性别特异性的方式。我们将：1）确定睾酮水平的增加如何影响tau蛋白 在具有人ApoE 4/E3基因敲入的雌性tau转基因小鼠模型中的发病机制; 2）阐明了与人类ApoE 4/E3基因敲入相关的分子机制。 单核RNA介导的睾酮对ApoE 4雌性动物保护作用的机制 测序，并确定神经元和星形胶质细胞雄激素受体信号传导的参与。这 该项目旨在缩小我们对tau蛋白性别差异机制的理解方面的关键差距 病理生理学，并提供了新的见解雄激素的影响的分子机制的核心， AD发病机制拟议研究的结果将解决NIA战略目标：了解 阿尔茨海默氏症的进展（A），并确定潜在的治疗目标，以发展精确的 男性和女性的药物治疗（D）。