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; 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.

阿尔茨海默氏病（AD）是一个严重的公共卫生问题。广告是痴呆的最常见原因，这是 病理学的特征是淀粉样蛋白斑块的积累和含tau的神经纤维缠结 在大脑中。广告在临床上表现为渐进记忆丧失和认知障碍，导致 长期残疾和最终死亡。然而，AD发病机理的基础机制并非完全 了解并且目前没有有效的疗法可用于广告。我们的初步数据指向重要角色 脉络丛（CHP）中的低密度脂蛋白受体相关蛋白相关蛋白1（LRP1）和tanycytes 对淀粉样β（A）和tau外排的最佳调节显着。我们发现在 CHP导致CSF的A清除率显着降低到循环。有趣的是，我们也发现 坦率的LRP1对于调节从CSF到血液的TAU清除率是必要的。重要的是，LRP1 响应于a或tau的瘦素受体（LEPR）物理结合。此外，我们观察到饮食引起的 营养不良会损害大脑的清除率，与肥胖相关的代谢参数负相关 具有短期记忆。因此，我们假设CHP和Tanycytes中的LRP1对于确定 A和Tau间隙，与LEPR结合以从CSF施加这些蛋白质的转胞膜 圆圈。这是LRP1作用受损会导致大脑中的A和Tau加速，从而导致AD。肥胖 进一步加剧了LRP1依赖性A和Tau外排，加速了认知能力下降。为此，我们将（i） 确定LRP1在控制脉络丛中A外排的作用； （ii）探索LRP1在 调节tanycytes的tau运输。为了实现这些目标，我们将采用最新的生化， 分子，细胞和代谢物理技术，包括基因工程组织特异性的 转基因小鼠模型，体内活体两光子成像和CRE诱导的AAV系统。这些研究会 提供一个独特的机会来建立一种新型机制，将LRP1作为A和 tau外排。从这些及时研究中产生的数据可能会为基本机制提供新的见解 lrp1依赖的A和tau的清除率在AD的病原体中，并为新的治疗靶标提供了 广告和相关痴呆症。