Role of LRP1 in Alzheimer’s disease

阿尔茨海默病(AD)是一个严重的公共卫生问题。AD是痴呆症最常见的原因，它 病理特征是淀粉样斑块和含有tau的神经原纤维缠结积聚。 在大脑里。AD的临床表现为进行性记忆丧失和认知障碍，导致 长期残疾和最终死亡。然而，AD发病的细胞机制还不完全清楚。 目前尚无治疗阿尔茨海默病的有效方法。我们的初步数据表明， 低密度脂蛋白受体相关蛋白1(LRP1)在脉络丛(CHP)和张力细胞中的表达 在淀粉样β蛋白(A)和tau外流的最佳调节中具有重要意义。我们发现LRP1的缺失在 CHP导致A-从脑脊液进入循环的清除量显著降低。有趣的是，我们还发现 Tanycell中的LRP1是调节tau从脑脊液到血液的清除所必需的。重要的是，LRP1 瘦素受体(Lepr)与瘦素受体(Lepr)结合，对A或Tau有反应。此外，我们观察到饮食诱导 营养过剩损害大脑对的清除与肥胖相关代谢参数呈负相关 有短期记忆的人。因此，我们假设CHP和Tanycell中的LRP1对于调节 和tau清除，它与LEPR偶联，将这些蛋白从脑脊液转胞到 发行量。因此，LRP1的作用受损会导致A和tau在大脑中积累，从而导致AD。肥胖 进一步加重LRP1依赖的A和tau外流，加速认知功能下降。为此，我们将(一) 确定LRP1在控制脉络丛A外流中的作用；(Ii)探讨LRP1在脉络丛中的意义。 调节柔韧细胞中tau的运输。为了实现这些目标，我们将采用最先进的生物化学， 分子、细胞和代谢生理学技术，包括基因工程组织特异性 转基因小鼠模型，活体双光子成像，Cre诱导的AAV系统。这些研究将 提供了一个独特的机会来建立一种新的机制，将LRP1作为的关键决定因素 牛磺酸外流。这些及时研究产生的数据可能会为潜在的机制提供新的见解 LRP1依赖的A和tau清除在AD发病机制中的作用 AD及相关痴呆症。

Alzheimer’s disease (AD) is a serious public health problem. AD is the most common cause of dementia, which is pathologically characterized by the accumulation of amyloid plaques and tau-containing neurofibrillary tangles in the brain. AD is clinically manifested as progressive memory loss and cognitive impairment, leading to prolonged disability and eventual death. Yet, the cellular mechanisms underlying AD pathogenesis are not fully understood and no effective therapy is currently available for AD. Our preliminary data point to the important role of low-density lipoprotein receptor-related protein 1 (LRP1) in the choroid plexus (ChP) and tanycytes that is significant in the optimal regulation of amyloid-beta (A) and tau efflux. We found that deletion of LRP1 in the ChP leads to a significant decrease in A clearance from the CSF into circulation. Interestingly, we also found that LRP1 in tanycytes is necessary to regulate tau clearance from the CSF to the blood. Importantly, LRP1 physically binds to leptin receptor (LepR) in response to A or tau. Furthermore, we observed that diet-induced overnutrition impairs A clearance from the brain and obesity-related metabolic parameters negatively correlate with short-term memory. We therefore hypothesize that LRP1 in the ChP and tanycytes is essential for regulating A and tau clearance, which is coupled with the LepR to exert transcytosis of these proteins from the CSF to circulation. Thus, an impaired LRP1 action causes A and tau accumulation in the brain, leading to AD. Obesity further aggravates LRP1-dependent A and tau efflux, accelerating cognitive decline. To this end, we will (i) establish the role of LRP1 in controlling A efflux in the choroid plexus; (ii) explore the significance of LRP1 in regulating tau transport in tanycytes. To accomplish these goals, we will employ state-of-the-art biochemical, molecular, cellular, and metabolic physiological techniques, including genetically engineered tissue-specific transgenic mouse models, in vivo live two-photon imaging, and Cre-inducible AAV system. These studies will provide a unique opportunity to establish a novel mechanism implicating LRP1 as a key determinant of A and tau efflux. The data generated from these timely studies may offer new insights into the underlying mechanisms of LRP1-dependent A and tau clearance in the etiopathogenesis of AD and provide new therapeutic targets for AD and related dementia.