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（AD）是一个严重的公共卫生问题，AD 是痴呆症的最常见原因。 病理学特征是淀粉样斑块和含 tau 蛋白的神经原纤维缠结的积累 AD在临床上表现为进行性记忆丧失和认知障碍，导致 然而，AD 发病机制的细胞机制尚不完全清楚。 我们的初步数据表明了 AD 的重要作用，但目前尚无有效的治疗方法。 脉络丛 (ChP) 和单细胞中低密度脂蛋白受体相关蛋白 1 (LRP1) 的含量 我们发现 LRP1 的缺失对淀粉样蛋白-β (A) 和 tau 流出的最佳调节具有重要意义。 我们还发现，ChP 导致 A 从 CSF 进入循环的清除率显着降低。 tanycytes 中的 LRP1 对于调节 tau 从 CSF 到血液的清除是必需的。 与瘦素受体（LepR）物理结合以响应 A 或 tau 此外，我们观察到饮食诱导的。 营养过剩会损害 A 从大脑中的清除率，与肥胖相关的代谢参数呈负相关 因此，我们发现 ChP 和 tanycytes 中的 LRP1 对于调节至关重要。 A 和 tau 清除，与 LepR 结合，发挥这些蛋白质从 CSF 的转胞吞作用 因此，LRP1 作用受损会导致 A 和 tau 蛋白在大脑中积聚，从而导致肥胖。 进一步加剧 LRP1 依赖性 A 和 tau 外流，加速认知能力下降。为此，我们将 (i) 确定 LRP1 在控制脉络丛 A 流出中的作用；(ii) 探索 LRP1 在控制脉络丛中的重要性； 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 这些研究将包括转基因小鼠模型、体内活体双光子成像和 Cre 诱导 AAV 系统。 提供了一个独特的机会来建立一种新颖的机制，将 LRP1 作为 A 的关键决定因素，并且 这些及时研究产生的数据可能为潜在机制提供新的见解。 LRP1 依赖性 A 和 tau 清除在 AD 发病机制中的作用，并为 AD 发病机制提供新的治疗靶点 AD 和相关痴呆症。