Role of LRP1 in Alzheimer’s disease

LRP1 在阿尔茨海默病中的作用

• 批准号: 10596290
• 负责人: YOUNG-BUM KIM
• 金额: $ 86.78万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596290
• 关键词: Abeta clearance; Acceleration; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavior; Binding; Biochemical; Biological Process; Blood; Blood Circulation; Brain; Cell membrane; Cessation of life; Circulation; Clinical; Complex; Coupled; Data; Dementia; Deposition; Development; Diet; Endocytosis; Endothelial Cells; Epithelial Cells; Fatty acid glycerol esters; Functional disorder; Genetic Engineering; Goals; High Fat Diet; Image; Impaired cognition; Impairment; In Vitro; Injections; LDL-Receptor Related Protein 1; Lipoprotein Receptor; Memory Loss; Memory impairment; Metabolic; Molecular; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Obesity; Overnutrition; Pathogenesis; Pathologic; Peptides; Physiological; Proteins; Public Health; Regulation; Research; Role; Route; Senile Plaques; Short-Term Memory; Structure of choroid plexus; System; Techniques; Testing; Tissue Engineering; Transgenic Mice; abeta deposition; dimer; disability; effective therapy; feeding; hyperphosphorylated tau; in vivo; inducible Cre; innovation; insight; interest; leptin receptor; loss of function; mouse model; neurodegenerative dementia; neuropathology; new therapeutic target; novel; novel strategies; overexpression; prevent; response; tau Proteins; tau aggregation; transcytosis; two-photon; uptake; vesicle transport

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.

阿尔茨海默病（Alzheimer's disease，AD）是一种严重的公共卫生问题。AD是痴呆症最常见的原因， 病理学特征为淀粉样斑块和含tau蛋白的神经元缠结的积累 在大脑中。AD临床表现为进行性记忆丧失和认知障碍，导致 长期残疾并最终死亡。然而，AD发病机制的细胞机制还不完全清楚， 但是，目前还没有有效的治疗方法可用于AD。我们的初步数据表明 低密度脂蛋白受体相关蛋白1（LRP 1）在脉络丛（ChP）和伸展细胞， 在淀粉样蛋白-β（A β）和tau流出的最佳调节中具有重要意义。我们发现，LRP 1的缺失， ChP导致从CSF进入循环的A β清除率显著降低。有趣的是，我们还发现 伸展细胞中的LRP 1是调节tau从CSF到血液的清除所必需的。重要的是，LRP 1 响应于A β或tau，与瘦素受体（LepR）物理结合。此外，我们观察到，饮食诱导 营养过剩会损害大脑中A β的清除，与肥胖相关的代谢参数呈负相关 有短期记忆因此，我们假设ChP和伸长细胞中的LRP 1对于调节 A β和tau清除，其与LepR偶联以发挥这些蛋白质从CSF至CSF的转胞吞作用。 流通因此，受损的LRP 1作用导致A β和tau在大脑中积累，导致AD。肥胖 进一步抑制LRP 1依赖性A β和tau外排，加速认知能力下降。为此，我们将（一） 建立LRP 1在控制脉络丛A β流出中的作用;（ii）探讨LRP 1在 调节伸长细胞中的tau转运。为了实现这些目标，我们将采用最先进的生化技术， 分子、细胞和代谢生理技术，包括基因工程组织特异性 转基因小鼠模型、体内活双光子成像和Cre诱导的AAV系统。这些研究将 提供了一个独特的机会，以建立一个新的机制，涉及LRP 1作为一个关键的决定因素， tau外排。从这些及时的研究中产生的数据可能会为潜在机制提供新的见解 LRP 1依赖的A β和tau蛋白清除在AD发病机制中的作用，并为AD的治疗提供了新的靶点。 AD和相关痴呆症。