Beta-Amyloid Clearance by Mammalian Choroid Plexus: Effect of Lead Exposure

哺乳动物脉络丛清除β-淀粉样蛋白：铅暴露的影响

• 批准号: 7777835
• 负责人: WEI ZHENG
• 金额: $ 18.39万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777835
• 关键词: Acute; Affect; Age-Months; Agreement; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Animals; Apical; Attention; Autopsy; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Cerebrospinal Fluid; Chronic; Data; Deposition; Diffuse; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Etiology; Event; Exposure to; Extracellular Fluid; Extracellular Space; General Population; Homeostasis; Human; In Situ; In Vitro; Indiana; Insulinase; Lead; Lipoprotein Receptor; Literature; Low Density Lipoprotein Receptor; Mediating; Metabolic; Metabolism; Methods; Microscope; Modeling; Mus; Neuraxis; Neurology; Neurons; Pathway interactions; Patients; Perfusion; Plague; Play; Process; Production; Regulation; Research; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Senile Plaques; Staining method; Stains; Structure of choroid plexus; Techniques; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Universities; Western Blotting; Work; abeta accumulation; age related; amyloid formation; base; basolateral membrane; blood cerebrospinal fluid barrier; brain tissue; cell injury; chronic Pb exposure; design; familial Alzheimer disease; in vivo; lead exposure; medical schools; novel; novel strategies; public health relevance; receptor; toxic metal; toxicant; uptake

DESCRIPTION (provided by applicant): Accumulation of beta-amyloid (A2) in brain extracellular fluids is the key event in the amyloid cascade leading to neuronal cell damage in the etiology of Alzheimer's disease (AD). Our preliminary data suggest that the choroid plexus sequesters A2 from the cerebrospinal fluid (CSF). The choroid plexus, as the tissue constituting the blood-CSF barrier, is also known to accumulate toxic metal lead (Pb) based on both human and animal studies. More recently, we found that acute in vivo Pb exposure increases A2 deposition in this tissue. Thus, this exploratory research proposal is designed to test the hypothesis that exposure to Pb results in an accumulation of beta-amyloids in the choroid plexus as well as in brain tissues; this may occur as a result of Pb alteration of beta-amyloid clearance by the choroid plexus by affecting beta-amyloid transport and/or enzymatic degradation in this tissue. Several techniques unique to the blood-brain barrier research such as in vitro two-chamber Transwell trans-epithelial model, in situ brain perfusion and in situ ventriculo-cisternal perfusion, along with transgenic mice that over-express A2, will be used to test the research hypothesis. The study proposed in this application will explore novel pathways of A2 clearance from brain extracellular fluids and will define the role of Pb exposure in these processes. Potential discovery of A2 transporters and metabolic regulatory mechanisms in the choroid plexus will help develop novel strategies for treatment and prevention of Alzheimer's disease. PUBLIC HEALTH RELEVANCE This study will explore novel pathways of A2 clearance from brain extracellular fluids and will define the role of Pb exposure in these processes. Results of this study will provide clues as to whether exposure to toxic metal lead (Pb) in the general population may contribute to the AD etiology. Potential discovery of A2 transporters and metabolic regulatory mechanism in the choroid plexus will help develop novel strategies for treatment and prevention of Alzheimer's disease.

描述（由申请人提供）：脑外流体中β-淀粉样蛋白（A2）的积累是淀粉样蛋白级联反应的关键事件，导致阿尔茨海默氏病（AD）病因学导致神经元细胞损伤。我们的初步数据表明，脉络丛隔离了脑脊液（CSF）的A2。脉络丛作为构成血液-CSF屏障的组织，也众所周知，基于人类和动物研究，会积累有毒金属铅（PB）。最近，我们发现急性体内PB暴露会增加该组织中的A2沉积。因此，该探索性研究建议旨在检验以下假设：暴露于PB会导致脉络丛和脑组织中β-淀粉样蛋白的积累。这可能是由于脉络膜丛链淀粉的β-淀粉样蛋白清除率改变而发生的，这可能会通过影响β-淀粉样蛋白转运和/或该组织中的酶促降解而导致。血脑屏障研究所独有的几种技术，例如体外的两腔Transwell跨层跨上皮模型，原位脑灌注和原位心室灌注以及过表达A2的转基因小鼠，将用于检验研究假设。该应用中提出的研究将探索来自脑外流体的A2清除率的新途径，并将定义PB暴露在这些过程中的作用。脉络丛中A2转运蛋白和代谢调节机制的潜在发现将有助于制定新的治疗和预防阿尔茨海默氏病的策略。公共卫生相关性本研究将探索来自脑外流体的A2清除率的新途径，并将定义PB暴露在这些过程中的作用。这项研究的结果将提供有关一般人群中有毒金属铅（PB）是否可能有助于AD病因的线索。脉络丛中A2转运蛋白和代谢调节机制的潜在发现将有助于制定新颖的治疗和预防阿尔茨海默氏病的策略。

项目成果

Decreased axonal density and altered expression profiles of axonal guidance genes underlying lead (Pb) neurodevelopmental toxicity at early embryonic stages in the zebrafish.

• DOI: 10.1016/j.ntt.2011.07.010
• 发表时间: 2011-11
• 期刊: NEUROTOXICOLOGY AND TERATOLOGY
• 影响因子: 2.9
• 作者: Zhang, Jun;Peterson, Samuel M.;Weber, Gregory J.;Zhu, Xinqiang;Zheng, Wei;Freeman, Jennifer L.
• 通讯作者: Freeman, Jennifer L.

Analysis of Blood Concentrations of Zinc, Germanium, and Lead and Relevant Environmental Factors in a Population Sample from Shandong Province, China.

中国山东省人群样本中锌、锗、铅的血液浓度及相关环境因素分析。

• DOI: 10.3390/ijerph14030227
• 发表时间: 2017
• 期刊: International journal of environmental research and public health
• 作者: Li,Long;Xu,Guang;Shao,Hua;Zhang,Zhi-Hu;Pan,Xing-Fu;Li,Jin-Ye
• 通讯作者: Li,Jin-Ye

Baseline blood levels of manganese, lead, cadmium, copper, and zinc in residents of Beijing suburb.

• DOI: 10.1016/j.envres.2015.03.008
• 发表时间: 2015-07
• 期刊: ENVIRONMENTAL RESEARCH
• 影响因子: 8.3
• 作者: Zhang, Long-Lian;Lu, Ling;Pan, Ya-Juan;Ding, Chun-Guang;Xu, Da-Yong;Huang, Chuan-Feng;Pan, Xing-Fu;Zheng, Wei
• 通讯作者: Zheng, Wei