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: 7793474
• 负责人: CONRAD Earl JOHANSON
• 金额: $ 30.65万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7793474
• 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：衰老严重干扰穿过血脑屏障 (BBB) 和血脑脊液界面的清除（重吸收）运输。因此，神经元的健康和功能会受到间质液（ISF）和脑脊液中的分解代谢物毒性（例如β淀粉样蛋白（Ap））的损害。有害的 ISF-CSF 相互作用可能会加剧衰老以及正常压力脑积水 (NPH) 和阿尔茨海默病 (AD)。工作假设：在 BBB 运输改变的情况下，衰老过程中 CSF 周转减少，导致 Ap 滞留在 CNS 中。衰老早期 BBB 中 Ap 清除转运蛋白、低密度脂蛋白受体相关蛋白 1 (LRP-1) 的表达减弱，引发病理生理级联反应，促进有毒 Ap40 和 Ap42 在大脑和脉络膜脑膜组织中的滞留。因此，脉络丛(CP)-CSF-蛛网膜连接的清除能力降低，导致Ap碎片在血管周围“屏障”界面和脑间隙中逐渐积累。实验范式：我们将探索 CP 和 BBB Ap 转运蛋白、CSF 动态和大脑 Ap 负担之间与年龄相关的功能关系。 Brown-Norway/Fischer 大鼠在 3、12、20、30 和 36 个月时将用于：i) 测量大脑中总 Ap 作为年龄的函数并描述其空间分布，ii) 量化标记 Ap 的清除动力学来自 CP-CSF 的衰老过程和乙酰唑胺或 FGF2 诱导的血流抑制后的结果，以及 Hi) 表征了 Ap 转运蛋白、LRP-1 和受体的年龄修饰表达随着脑脊液系统不断恶化，CP 和 BBB 中的高级糖基化终产物 (RAGE)。 CSF形成率/体积将通过脑室脑池灌注中蓝色右旋糖酐的稀释来确定。标记的 Ap 的 CP 运输和 CSF 周转率的与年龄相关的变化将通过 ANCOVA 和多重范围进行分析，并测试与 Ap 片段、LRP-1 和 RAGE 的改变（大脑和脑膜）的关联。将通过 IHC、ELISA、蛋白质印迹和实时 PCR 评估肽/蛋白质。空间、时间和动力学（运输）数据将阐明导致肽通过衰老 CP-CSF-BBB 系统从大脑中清除不足的病理序列。翻译：Ap 是分析老化对 ISF-CSF 关系的影响以及屏障系统故障导致的溶质清除受损的权宜标记。这揭示了神经退行性疾病。