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

• 批准号: 10302046
• 负责人: VAHRAM HAROUTUNIAN
• 金额: $ 126.84万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10302046
• 关键词: 3xTg-AD mouse; Affect; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Amyloid beta-Protein Precursor; Antibodies; Architecture; Area; Asparagine; Automobile Driving; Blocking Antibodies; Blood; Body fat; Brain; Brain region; Bypass; Cells; Cholesterol; Cleaved cell; Clinical; Cognitive; Complement; Coupled; Data; Dementia; Discipline; Disease; Endocrinology; Endopeptidases; Energy Metabolism; Estrogen Replacements; Estrogens; Evaluation; Evolution; Fatty acid glycerol esters; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Future; Genetic study; Goals; Gonadal structure; Health Hazards; Hippocampus (Brain); 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; 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; base; bone; bone cell; bone loss; brain tissue; cognitive function; design; disease phenotype; endopeptidase A; 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

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.

项目总结 阿尔茨海默病(AD)突出表现在两个方面--无法治愈和影响 女人比男人多。虽然雌激素的下降被认为是绝经后AD的基础，但还有 AD与卵泡刺激素(FSH)水平升高有明显的临床相关性。最值得注意的是，有 绝经过渡期早期女性认知能力下降的“高峰”，此时血清雌激素 正常和FSH水平开始上升。西奈山和埃默里研究小组之间的合作研究 发现FSH是AD的潜在驱动因素，并提示FSH水平的上升可能有助于 AD在老年女性中的不成比例增加。值得注意的是，我们发现FSH受体(FSHR)表达 在小鼠和人脑中，注射重组FSH或卵巢切除(这会提高血清水平) FSH)可加重3xTg小鼠的AD病理和认知功能减退。抑制FSH在3xTg中的作用 APP/PS1小鼠通过FSH封闭抗体或下调FSHR在海马区的表达来预防 AD表型的发病。埃默里研究小组还提供了强有力的初步证据，表明FSH上调 C/eBPβ，激活天冬酰胺内肽酶，天冬酰胺内肽酶是一种裂解淀粉样前体的δ分泌酶 蛋白质(APP)和Tau--分别导致神经炎斑块和神经原纤维缠结。的目标是 内分泌学和神经科学学科之间的跨学科合作是充分 了解FSH对阿尔茨海默病易感脑区的作用机制。因此，在具体目标1中，我们将 FSHR及其信号伙伴CEBPB和LGMN在人体内的分布和细胞定位 以及使用单转录技术的小鼠大脑。在具体目标2中，我们将研究 脑FSHR在AD病理和认知功能下降中的作用为此，我们将下调或过度表达 通过立体定向注射表达siFshr或FSHR的AAV，在3xTg小鼠的特定脑区注射FSHR。我们还将 研究高FSH对CEBPB单倍体缺乏的3xTg小鼠的影响，并描绘其转录水平 应用RNA-seq技术构建FSH处理的人神经细胞。在具体目标3中，我们将确定是否 我们的小鼠FSH阻断抗体HF2终生注射可消除FSHR或抑制FSH的作用 3xTg小鼠可预防认知功能减退的发生。同时复制我们的数据，埃默里 研究小组将研究在18个月大的APP中使用HF2治疗已建立的认知障碍的效果 (Ki)小鼠。总之，我们的概念验证研究--使用我们的良好实验室实践(GLP)进行的 平台--不仅要确立高FSH在推动AD中的作用，而且要为未来提供一个框架 我们人源化的FSH阻断抗体HU6在老年妇女中的测试。