Atlas of CSF tau clearance pathways in the aging brain and in Alzheimer's disease

衰老大脑和阿尔茨海默病中 CSF tau 清除途径图谱

• 批准号: 9429378
• 负责人: RASHID DEANE
• 金额: $ 191.12万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9429378
• 关键词: APP-PS1; Affect; Age; Aging; Albumins; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Antibodies; Area; Atlases; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebrospinal Fluid; Cervical; Cervical lymph node group; Cognition; Confocal Microscopy; Contrast Media; Convection; Data; Deposition; Drainage procedure; Dura Mater; Fluorescein-5-isothiocyanate; Fluorescence; Gadolinium; Gadolinium DTPA; Human; Image; Injectable; Intercellular Fluid; Kinetics; Lead; Liquid substance; Lymph; Lymphatic; Lymphatic System; Lymphatic vessel; Magnetic Resonance Imaging; Maps; Mus; Nerve; Neurocognitive Deficit; Nose; Pathology; Pathway interactions; Pattern; Process; Proteins; Role; Route; Sinus; Spinal Cord; Subarachnoid Space; Techniques; Testing; Therapeutic; Time; Tissues; Tsunami; Water; age related; aging brain; cerebrospinal fluid flow; cisterna magna; cranium; improved; in vivo; lateral ventricle; macromolecule; monomer; mouse model; novel; novel therapeutics; olfactory bulb; tau Proteins

Abstract Since there are no lymphatic vessels in brain, cerebrospinal fluid (CSF), the pseudo-lymphatic system, flows around the brain and eliminates protein macromolecules to blood by many routes. The turnover of CSF is reduced with aging and in Alzheimer’s disease (AD). This contributes to the accumulation of protein macromolecules, especially those that are not transported across the blood brain barrier (BBB), such as tau proteins that are associated with AD. However, it’s unclear whether age and AD differential affect the various CSF drainage routes. We used a new protein macromolecule, gadolinium (Gd)-albumin-FITC, as the contrast agent for MRI, followed by fluorescence analysis of the same molecule to specifically delineate macromolecule clearance via CSF flow. Our preliminary data show differences between CSF distribution pattern using Gd- DTPA (standard contrast agent) and Gd-albumin-FITC, with the latter effectively representing the main CSF flow pathways. The distribution of Gd-albumin-FITC in the olfactory bulb, nasal areas, spinal cord and cervical lymph nodes was reduced in APP/PS1 mice compared to normal mice. Tau, brain derived protein, was distributed from brain to CSF and cleared via the cervical lymphatic pathways. CSF flow increased clearance from brain. We hypothesized that Gd-abumin-FITC will effectively assess changes in CSF macromolecule clearance, and thus, will identify clearance pathways of tau proteins that is susceptible to aging. Three aims are proposed to test this hypothesis in aging APP/PS1 mice (2 and 12 months old). Aim 1. Assess CSF clearance pathways in aging APP/PS1 mice using MRI and fluorescence analyses. Aim 2. Assess tau protein clearance via CSF pathways in aging APP/PS1 mice. Aim 3. Assess the efficacy of CSF drainage on tau clearance in aging APP/PS1 mice. The kinetics of macromolecule distribution and elimination in CSF will be determined by using mainly non-invasive techniques, MRI and fluorescence analysis of the same molecule, Gd-albumin-FITC, and near infra-red (NIR)-tau fluorescence. These in vivo real-time imaging followed by confocal microscopy will delineate the CSF flow pathways, CSF/ISF and ISF/CSF exchange and tau clearance pathways. Maps of 3D atlases will identify age/AD-dependent rate limiting pathways. APP/PS1 mice will be used to test the role of amyloid-β in tau clearance in the absence of endogenous human tau oligomerzation. We expect the data will show that tau (monomer>fibril) is cleared by CSF pathways, involving convective flow of ISF, the perivascular space and mainly the cervical lymph, in mice. Aging and Aβ levels will reduce while increasing CSF flow will enhance tau clearance. Simultaneous studying all the CSF pathways will be unbiased, rigorous and objective in identifying the CSF pathway affected by age/AD, i.e., therapeutic windows, which would lead to novel targets to enhance CSF/tau clearance in the aging brain so as to slow AD related neurocognitive decline and the pending AD tsunami.

摘要 由于大脑中没有淋巴管，因此脑脊液（CSF），即假淋巴系统， 并通过多种途径将蛋白质大分子清除到血液中。CSF的周转率为 随着年龄的增长和阿尔茨海默病（AD）的发生而减少。这有助于蛋白质的积累 大分子，特别是那些不通过血脑屏障（BBB）转运的大分子，如tau蛋白 与AD相关的蛋白质然而，目前还不清楚年龄和AD差异是否会影响各种 脑脊液引流路径。我们用一种新的蛋白质大分子钆（Gd）-白蛋白-FITC作对照 用于MRI的试剂，随后对相同分子进行荧光分析以特异性地描绘大分子 通过CSF流清除。我们的初步数据显示，使用Gd的CSF分布模式之间存在差异， DTPA（标准造影剂）和Gd-白蛋白-FITC，后者有效代表主要CSF 流动路径。Gd-albumin-FITC在大鼠嗅球、鼻区、脊髓和颈部的分布 与正常小鼠相比，APP/PS1小鼠的淋巴结减少。Tau，脑源性蛋白， 从脑分布到CSF并通过颈淋巴途径清除。CSF流量增加清除率 从大脑。我们假设Gd-abumin-FITC将有效评估CSF大分子的变化， 清除，并因此将鉴定对老化敏感的tau蛋白的清除途径。三个目标 提出在老龄APP/PS1小鼠（2和12个月大）中检验这一假设。目标1.评估CSF 使用MRI和荧光分析在老化APP/PS1小鼠中的清除途径。目标2.评估tau 在老化APP/PS1小鼠中通过CSF途径的蛋白质清除。目标3。评估CSF的疗效 排水对老化APP/PS1小鼠中tau清除的影响。大分子分布动力学和 将主要使用非侵入性技术、MRI和荧光分析确定CSF中的消除 相同分子的Gd-白蛋白-FITC和近红外（NIR）-tau荧光。这些体内实时 成像后进行共聚焦显微镜检查将描绘CSF流动路径、CSF/ISF和ISF/CSF 交换和tau清除途径。3D图谱将识别年龄/AD依赖性心率限制 途径。APP/PS1小鼠将用于测试淀粉样蛋白-β在tau清除中的作用， 内源性人tau寡聚化。我们预计数据将显示tau（单体>原纤维）被清除， CSF通路，涉及小鼠中ISF、血管周围空间和主要颈淋巴的对流。 衰老和Aβ水平将降低，而增加CSF流量将增强tau清除。同时学习 所有CSF途径在确定受以下因素影响的CSF途径时将是无偏倚、严格和客观的 年龄/AD，即，治疗窗口，这将导致新的目标，以提高CSF/tau清除在 从而减缓AD相关的神经认知衰退和即将到来的AD海啸。