Role of tanycytic LRP in Aβ clearance

此应用程序对应于特别关注的通知：针对阿尔茨海默氏症的行政补充 NIH不专注于阿尔茨海默氏症的拨款。阿尔茨海默病(AD)是一种进行性的 以记忆丧失、认知受损和最终功能障碍为特征的神经退行性疾病 伤残和死亡。据估计，AD影响了美国580万人，新增病例达50万 每年，这个数字预计将在30年内翻一番以上。鉴于...的显著增长 阿尔茨海默病在成人人群中的流行，确定治疗和预防阿尔茨海默病的新目标，以及 迫切需要与之相关的痴呆症。AD发病的标志是淀粉样蛋白-的积聚 多肽(A)：大脑中神经细胞之间的斑块。A的积累是A失衡的结果 淀粉样前体蛋白的生成及其随后的清除。受损的清除主要是 导致其在散发性或迟发性AD中积聚，而不是A的生产过剩。低密度 脂蛋白受体相关蛋白-1或-2在清除脑内中的作用是通过促进 星形胶质细胞、神经元和脑血管平滑肌细胞对的摄取和降解以及的转胞作用 穿过血脑屏障。然而，在理解基础上的中央机制方面存在一个重大差距 LRP1/2介导的清除一直缺乏关于LRP1/2如何调节消除的知识 在下丘脑的松弛细胞中。这可能是由于缺乏合适的动物模型来研究LRP1/2 在体内清除的背景下在tanyctes中的作用。在父母助学金的研究期间 (R01DK12302，Control of Leptin Transport System by LRP)，我们建立了LRP2缺失的小鼠 用Rax-CreERT2基因敲除小鼠(Rax-CreERT2；LRP2loxP/loxP)培育LRP2loxP/loxP。我们也是 目前通过用Rax-CreERT2小鼠(Rax-CreERT2)培育LRP1loxP/loxP来创造在松弛细胞中缺乏LRP1的小鼠(Rax-CreERT2)。 CRERT2；LRP1loxP/loxP)。利用这些模型，我们将检验这一新的假设，即LRP1/2在小鼠的伸缩细胞中 下丘脑是必需的，以清除A从脑到血流和LRP1/2的功能障碍 张力细胞会导致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 进一步深入了解AD相关疾病的发病机制，为AD相关疾病的治疗提供新的靶点 治疗阿尔茨海默病。

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.