Role of tanycytic LRP in Aβ clearance

tanycytic LRP 在 Aβ 清除中的作用

• 批准号: 10281970
• 负责人: YOUNG-BUM KIM
• 金额: $ 43.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10281970
• 关键词: Abeta clearance; Address; Administrative Supplement; Adult; Affect; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animal Model; Apolipoproteins; Astrocytes; Blood - brain barrier anatomy; Blood Circulation; Brain; Breeding; Cessation of life; Data; Dementia; Disease; Ependymal Cell; Functional disorder; Generations; Goals; Grant; Hypothalamic structure; Impaired cognition; Impairment; Knock-in Mouse; Knowledge; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Lead; Leptin; Link; Mediating; Memory Loss; Modeling; Mus; Neurodegenerative Disorders; Neurons; Pathogenesis; Peptides; Physiological; Play; Population; Prevalence; Prevention strategy; Protein Precursors; Regulation; Research; Role; Route; Smooth Muscle Myocytes; Structure of choroid plexus; System; Testing; United States; United States National Institutes of Health; amyloid peptide; cerebrovascular; energy balance; functional disability; in vivo; in vivo Model; insight; interest; new therapeutic target; novel; parent grant; prevent; recombinase-mediated cassette exchange; transcytosis; uptake

This application corresponds to Notice of Special Interest: Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s diseases. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by memory loss, impaired cognition and eventual functional disability and death. AD affects an estimated 5.8 million people in the United States with half a million new cases annually, and this number is anticipated to more than double within 30 years. Given the significant increase in the prevalence of AD in the adult populations, identification of novel targets for treating and preventing AD and its related dementias is urgently needed. The hallmark of AD pathogenesis is the accumulation of amyloid- peptide (A) plaques between nerve cells in the brain. The A accumulation is the result of an imbalance of A generation in amyloid precursor protein and its subsequent clearance. Impaired A clearance is predominantly responsible for its accumulation in sporadic or the late-onset AD rather than A overproduction. The low-density lipoprotein receptor-related protein-1 or -2 (LRP1 or LRP2) plays a role in eliminating A in the brain by promoting A uptake and degradation in astrocytes, neurons and cerebrovascular smooth muscle cells, and A transcytosis across the blood brain barrier. However, a major gap in understanding the central mechanisms underlying LRP1/2-mediated A clearance has been a lack of knowledge regarding how LRP1/2 regulates A elimination in the hypothalamic tanycytes. This could be due to a lack of an appropriate animal model that can study LRP1/2 function in the tanyctes in the context of A clearance in vivo. During the research period of the parent grant (R01DK12302, Control of leptin transport system by LRP), we have generated the mice lacking LRP2 in the tanycytes by breeding LRP2loxP/loxP with Rax-CreERT2 Knock-in mice (Rax-CreERT2; LRP2loxP/loxP). We are also currently creating the mice lacking LRP1 in the tanycytes by breeding LRP1loxP/loxP with Rax-CreERT2 mice (Rax- CreERT2; LRP1loxP/loxP). Using these models, we will test the novel hypothesis that LRP1/2 in the tanycytes of the hypothalamus is necessary to clear A from the brain to the bloodstream and dysfunction of LRP1/2 in the tanycytes leads to A accumulation in the brain, leading to AD. The data generated from these studies may offer further insights into the pathogenesis of AD-related disorders and lead to new therapeutic targets for the treatment of AD.

此应用程序对应于特别关注的通知：针对阿尔茨海默病的行政补充 NIH 的资助不针对阿尔茨海默氏病 (AD)，它是一种进展性疾病。 神经退行性疾病，其特征是记忆丧失、认知受损和最终功能障碍 AD 影响了美国约 580 万人，新增病例达 50 万。 每年，考虑到这一数字的显着增长，预计 30 年内这一数字将增加一倍以上。 成人中 AD 的患病率、治疗和预防 AD 的新靶标的确定以及 AD 发病机制的标志是淀粉样蛋白- 的积累。 大脑神经细胞之间的肽 (A) 斑块 A 积累是 A 不平衡的结果。 淀粉样前体蛋白的产生及其随后的清除受损是主要的。 其在散发性或迟发性 AD 中的积累负责，而不是 A 的低密度生产过剩。 脂蛋白受体相关蛋白-1或-2（LRP1或LRP2）通过促进消除大脑中的A发挥作用 星形胶质细胞、神经元和脑血管平滑肌细胞中的 A 摄取和降解，以及 A 转胞吞作用 然而，在理解其核心机制方面存在重大差距。 LRP1/2介导的A清除一直缺乏关于LRP1/2如何调节A消除的知识 这可能是由于缺乏可以研究 LRP1/2 的合适动物模型。 在母基金的研究期间，在 A 体内清除的情况下，tanyctes 中的功能。 （R01DK12302，LRP对瘦素转运系统的控制），我们已经产生了缺乏LRP2的小鼠 通过将 LRP2loxP/loxP 与 Rax-CreERT2 敲入小鼠（Rax-CreERT2；LRP2loxP/loxP）繁殖来产生 tanycytes。 目前通过将 LRP1loxP/loxP 与 Rax-CreERT2 小鼠 (Rax- 使用这些模型，我们将测试 LRP1/2 在单细胞中的新假设。 下丘脑对于清除 A 从大脑到血液中所必需的以及 LRP1/2 的功能障碍 tanycytes 会导致 A 在大脑中积聚，从而导致 AD。这些研究产生的数据可能会提供帮助。 进一步深入了解 AD 相关疾病的发病机制，并为 AD 相关疾病找到新的治疗靶点 AD 的治疗。