Elevated FSH - A Driver for Sex Differences in Alzheimer's Disease

FSH 升高——阿尔茨海默病性别差异的驱动因素

基本信息

批准号：
10685326
负责人：
VAHRAM HAROUTUNIAN
金额：
$ 126.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685326
关键词：
3xTg-AD mouse Affect Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Amyloid beta-Protein Precursor Antibodies Antibody-mediated protection Architecture Area Asparagine Automobile Driving Blocking Antibodies Blood Body fat Brain Brain region Bypass Cells Cholesterol Clinical Cognitive Complement Coupled Data Dementia Discipline Disease Disparate Endocrinology Endopeptidases Energy Metabolism Estrogen Replacements Estrogen decline Estrogens Evaluation Evolution Fatty acid glycerol esters Female Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Future Genetic study Goals Gonadal structure Health Hazards Hippocampus Histocytochemistry Hormones Human Impaired cognition Injections Knock-in Mouse Life Longevity Maps Medical Menopause Mus Nature Neurofibrillary Tangles Neurons Neurosciences Obesity Organ Osteoporosis Ovariectomy Pathogenesis Pathway interactions Perimenopause Phase Phenotype Physiology Pituitary Hormones Postmenopause Proto-Oncogene Proteins c-akt Public Health Recombinant Follicle Stimulating Hormone Rodent Role Senile Plaques Serum Sex Differences Signal Transduction Small Interfering RNA Specific qualifier value Symptoms Technology Testing Textbooks Thyroid Gland Thyrotropin Transcript Treatment Protocols Up-Regulation Woman abeta accumulation aged bone bone loss brain tissue cognitive function design disease phenotype energy balance good laboratory practice hormonal signals hypercholesterolemia interdisciplinary collaboration knock-down laser capture microdissection loss of function male men mild cognitive impairment mouse model overexpression polyclonal antibody prevent receptor expression secretase small hairpin RNA tau Proteins transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) stands out as notable in two respects––in not having a cure and in affecting women more than men. While declining estrogen has been thought to underpin post–menopausal AD, there is a clear clinical correlation of AD with rising levels of follicle–stimulating hormone (FSH). Most notably, there is a ‘spike’ in cognitive decline in women in the early years of the menopausal transition, when serum estrogen is normal and FSH levels begin to rise. Collaborative studies between the Mount Sinai and Emory groups have identified FSH as a potential driver for AD—and suggest that rising FSH levels may contribute to the disproportionate increase of AD in aging women. Notably, we find that FSH receptors (FSHRs) are expressed in both mouse and human brain, and that the injection of recombinant FSH or ovariectomy (that elevates serum FSH) aggravates AD pathology and cognitive decline in 3xTg mice. Inhibiting the action of FSH in 3xTg or APP/PS1 mice by an FSH–blocking antibody or downregulating Fshr expression in the hippocampus prevents onset of the AD phenotype. The Emory group also provides strong preliminary evidence that FSH upregulates C/EBPβ, which activates asparagine endopeptidase (AEP), a δ–secretase that cleaves amyloid precursor protein (APP) and Tau––resulting in neuritic plaques and neurofibrillary tangles, respectively. The goal of the transdisciplinary collaboration between the disciplines of endocrinology and neuroscience is to fully understand the mechanism of FSH action on AD–vulnerable brain regions. Thus, in Specific Aim 1, we will map the distribution and cellular localization of the FSHR and its signaling partners CEBPB and LGMN in human and mouse brain using single–transcript technologies. In Specific Aim 2, we will examine the function of the brain FSHR in driving AD pathology and cognitive decline. For this, we will downregulate or overexpress the Fshr in specific brain areas of 3xTg mice by stereotaxically injecting AAV expressing siFshr or Fshr. We will also study the effect of high FSH in 3xTg mice rendered haploinsufficient in Cebpb, and delineate the transcriptomic architecture of FSH–treated human neuronal cells by RNA–seq. In Specific Aim 3, we will determine whether deleting the Fshr or inhibiting FSH action by our murine FSH blocking antibody, Hf2, injected over the lifespan of 3xTg mice can prevent the onset of cognitive decline. To contemporaneously replicate our data, the Emory group will study the effect of treating established cognitive impairment with Hf2 in 18–month–old APP knock–in (KI) mice. In all, our proof–of–concept studies––conducted using our Good Laboratory Practices (GLP) Platform––should not only establish a role for high FSH in driving AD, but also provide a framework for the future testing of our humanized FSH–blocking antibody, Hu6, in aging women.

项目摘要阿尔茨海默氏病（AD）在两个方面都引人注目 - 无法治愈，并影响女人比男人更多。虽然人们认为雌激素的下降是基于 - 绝经后的AD的基础 AD与叶片刺激的马龙（FSH）的临床相关性明显。最值得注意的是，有在更年期过渡的早期，女性认知下降的“尖峰”，血清雌激素是正常和FSH水平开始上升。西奈山和埃默里山之间的合作研究已有确定FSH是AD的潜在驱动因素，并建议FSH水平上升可能有助于老年妇女的AD不成比例增加。值得注意的是，我们发现表达FSH受体（FSHR）在小鼠和人脑，并注射重组FSH或卵巢切除术（这可以提升连续 FSH）加剧了3XTG小鼠的AD病理和认知下降。抑制FSH在3XTG或通过FSH烧阻抗体或海马中的FSHR表达下调的APP/PS1小鼠可防止 AD表型的发作。 Emory组还提供了强大的初步证据表明FSH上调 C/EBPβ激活天冬酰胺内肽酶（AEP），一种裂解淀粉样蛋白前体的δ-分泌酶蛋白质（APP）和Tau - 分别在神经质斑块和神经原纤维缠结中进行了反应。目标的目标内分泌学学科与神经科学学科之间的跨学科合作是完全了解FSH作用对AD可渗透大脑区域的机制。在特定的目标1中，我们将在人类中绘制FSHR及其信号伴侣CEBPB和LGMN的分布和细胞定位和小鼠大脑使用单一转录技术。在特定目标2中，我们将检查脑FSHR推动AD病理学和认知能力下降。为此，我们将下调或过表达通过对象注射AAV表达SIFSHR或FSHR，FSHR在3XTG小鼠的特定大脑区域中。我们也会研究高FSH在3XTG小鼠中的效果，使CEBPB充满单倍弹性，并描绘了转录组通过RNA – Seq进行FSH处理的人神经元细胞的结构。在特定目标3中，我们将确定是否通过我们的鼠FSH阻塞抗体HF2删除FSHR或抑制FSH动作，并在寿命上注射 3XTG小鼠可以防止认知能力下降。为了重复我们的数据，emory 小组将研究在18个月 - 售出的App敲击中使用HF2治疗已建立的认知障碍的效果（ki）小鼠。总的来说，我们使用我们的良好实验室实践（GLP）进行了证明 - 概念研究 - 进行了传导平台 - 不仅应该确立高FSH在驾驶广告中的作用，而且还为未来提供了一个框架对衰老的女性进行人源化FSH烧毁抗体Hu6的测试。