Age-Related Decrease in A-Beta Peptide Clearance Pathways: CSF and BBB

A-β 肽清除途径与年龄相关的减少：CSF 和 BBB

• 批准号: 7569456
• 负责人: CONRAD Earl JOHANSON
• 金额: $ 31.14万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569456
• 关键词: AP40; Acetazolamide; Address; Advanced Glycosylation End Products; Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Antibodies; Apis; Arachnoid mater; Attenuated; Blood; Blood - brain barrier anatomy; Brain; Carrier Proteins; Cerebrum; Choroid Plexus Epithelium; Data; Down-Regulation; Elderly; Endothelium; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial; Extracellular Fluid; FGF2 gene; Gap Junctions; Health; Hippocampus (Brain); Image; In Situ; In Vitro; Inbred F344 Rats; Intercellular Fluid; Kinetics; LDL-Receptor Related Protein 1; Light; Lipoprotein Receptor; Liquid substance; Measures; Meningeal; Meninges; Modeling; Nerve Degeneration; Neurons; Normal Pressure Hydrocephalus; Norway; Pathway interactions; Pattern; Peptides; Performance; Perfusion; Process; Proteins; RNA; Rattus; Research Personnel; Spatial Distribution; Structure of choroid plexus; System; Testing; Time; Tissues; Toxic effect; Translations; Ventricular; Western Blotting; Work; age effect; age group; age related; aging brain; blue dextran; cerebrovascular; equilibration disorder; frontal lobe; loss of function; neurochemistry; receptor; senescence; solute

DESCRIPTION (provided by applicant): Overview: Aging profoundly disturbs clearance (reabsorptive) transport across the blood-brain barrier (BBB) and blood-CSF interfaces. Consequently, neuronal health and function are impaired by catabolite toxicity, e.g., beta amyloid (Ap), in the interstitial fluid (ISF) and CSF. Detrimental ISF-CSF interactions may exacerbate aging as well as normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD). Working hypothesis: Decreased CSF turnover in senescence, in the setting of altered BBB transport, leads to Ap retention in the CNS. Attenuated expression of the Ap-clearance transporter, the low density lipoprotein receptor-related protein-1 (LRP-1), in the BBB in early aging triggers a pathophysiological cascade promoting retention of toxic Ap40 and Ap42 in the brain and choroido-meningeal tissues. Thus the clearance abilities of the choroid plexus (CP)-CSF-arachnoid nexus are reduced, leading to a progressive buildup of Ap fragments at perivascular 'barrier' interfaces and in the brain interstices. Experimental paradigm: We will explore age-related functional relationships among CP and BBB Ap transporters, CSF dynamics and brain Ap burden. Brown-Norway/Fischer rats at 3,12, 20, 30 and 36 mo will be used to: i) measure total Ap in brain as a function of age and describe its spatial distribution, ii) quantify the kinetics of clearance of tagged Ap from the CP-CSF in aging and after flow inhibition induced by acetazolamide or FGF2, and Hi) characterize the age-modified expression of the Ap transporters, LRP-1 and the receptor for advanced glycation end products (RAGE), in CP and BBB, as the CSF system continually deteriorates. CSF formation rate/volume will be determined by dilution of blue dextran in ventriculo-cisternal perfusion. Age-related changes in CP transport of tagged Ap and CSF turnover rate will be analyzed by ANCOVA and multiple range and tested for associations with alterations (brain and meninges) in Ap fragments, LRP-1 and RAGE. Peptides/proteins will be assessed by IHC, ELISA, Western blots and real time PCR. Spatial, temporal and kinetic (transport) data will elucidate pathological sequences leading to deficient peptide clearance from the brain via the senescent CP-CSF-BBB system. Translation: Ap is an expedient marker to analyze aging effects on ISF-CSF relationships, and the compromised solute clearance by malfunctioning barrier systems. This sheds light on neurodegeneration.

描述（由申请人提供）：概述：衰老深处干扰清除（重吸收）跨血脑屏障（BBB）和血液-CSF界面。因此，神经元健康和功能受到分解代谢物毒性的损害，例如β-淀粉样蛋白（AP），间质液（ISF）和CSF。有害的ISF-CSF相互作用可能会加剧老化以及正常压力脑积水（NPH）和阿尔茨海默氏病（AD）。工作假设：在BBB转运改变的情况下，衰老中CSF的周转率降低，导致CNS的AP保留。在早期衰老的BBB中，AP清除转运蛋白，低密度脂蛋白受体相关蛋白-1（LRP-1）的减弱表达触发了病理生理级联，从而促进了脑和脑脑膜内组织中毒性AP40和AP42的保留。因此，脉络丛（CP）-CSF-Arachnoid Nexus的清除能力降低，从而导致血管“屏障”接口和大脑间接处的AP片段逐渐累积。实验范式：我们将探索CP和BBB AP转运蛋白，CSF动力学和脑AP负担之间与年龄相关的功能关系。 Brown-Norway/Fischer rats at 3,12, 20, 30 and 36 mo will be used to: i) measure total Ap in brain as a function of age and describe its spatial distribution, ii) quantify the kinetics of clearance of tagged Ap from the CP-CSF in aging and after flow inhibition induced by acetazolamide or FGF2, and Hi) characterize the age-modified expression of the Ap transporters, LRP-1 and CP和BBB中的晚期糖基化最终产物（RAGE）受体，因为CSF系统不断恶化。 CSF的形成率/体积将由蓝色葡萄糖在心室灌注中稀释。标记为AP和CSF周转率的CP转运与年龄相关的变化将由ANCOVA和多个范围分析，并测试了与AP片段，LRP-1和RAGE中改变（大脑和脑膜）的关联（大脑和脑膜）。肽/蛋白质将由IHC，ELISA，Western印迹和实时PCR评估。空间，时间和动力学（传输）数据将通过衰老的CP-CSF-BBB系统阐明导致大脑肽清除不足的病理序列。翻译：AP是一个权宜标记，用于分析对ISF-CSF关系的衰老影响，以及通过故障障碍系统造成的溶质清除率。这阐明了神经变性。