Role of tanycytic LRP in Aβ clearance

此应用程序对应于特别关注的通知：阿尔茨海默氏症为重点的行政补充 美国国立卫生研究院的赠款并不集中在老年痴呆症上。阿尔茨海默病（AD）是一种进行性疾病， 神经退行性疾病，其特征在于记忆丧失、认知受损和最终的功能障碍。 残疾和死亡。在美国，AD影响着大约580万人，其中有50万新病例 每年，这个数字预计在30年内将增加一倍以上。鉴于 AD在成年人群中的患病率，治疗和预防AD的新靶点的确定， 其相关的痴呆症是迫切需要的。AD发病机制的标志是淀粉样蛋白的积累， 脑内神经细胞之间的肽（A β）斑块。A β积累是A β失衡的结果 淀粉样前体蛋白的生成及其随后的清除。A β清除率受损主要是 负责其在散发性或迟发性AD中的积累，而不是A β的过度产生。低密度 脂蛋白受体相关蛋白-1或-2（LRP 1或LRP 2）在消除脑中的A β中起作用， A β在星形胶质细胞、神经元和脑血管平滑肌细胞中的摄取和降解，以及A β转胞吞 穿过血脑屏障然而，在理解其核心机制方面存在重大差距， LRP 1/2介导的A β清除一直缺乏关于LRP 1/2如何调节A β清除的知识 在下丘脑的伸长细胞中。这可能是由于缺乏适当的动物模型，可以研究LRP 1/2 在体内A β清除的背景下在tanycte中起作用。在父母补助金的研究期间 （R 01 DK 12302，LRP对瘦素转运系统的控制），我们已经产生了缺乏LRP 2的小鼠。 通过用Rax-CreERT 2敲入小鼠（Rax-CreERT 2; LRP 2loxP/loxP）繁殖LRP 2loxP/loxP。我们也 目前通过将LRP 1 loxP/loxP与Rax-CreERT 2小鼠（Rax-CreERT 2小鼠）交配， CreERT2; LRP 1 loxP/loxP）。使用这些模型，我们将测试新的假设，LRP 1/2在伸长细胞的 下丘脑是必要的，以清除从大脑到血液和LRP 1/2的功能障碍， 伸长细胞导致AD在脑中积聚，导致AD。这些研究产生的数据可能提供 进一步了解AD相关疾病的发病机制，并为AD相关疾病的治疗提供新的靶点。 治疗AD。

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.