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Defining the role of age-related glymphatic pathway impairment in amyloid beta plaque deposition

定义年龄相关的类淋巴通路损伤在淀粉样β斑块沉积中的作用

基本信息

批准号：
10198706
负责人：
Jeffrey J Iliff
金额：
$ 34万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198706
关键词：
Abeta clearance Abeta synthesis Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid beta-Protein Astrocytes Biological Assay Blood Circulation Brain Brain region Cerebellum Cerebrospinal Fluid Cerebrovascular system Clinical Dementia Dependovirus Deposition Development Disease Elderly Event Face Genes Genetic Hippocampus (Brain)Histologic Human Image Impairment Incidence Intercellular Fluid Kinetics Lead Liquid substance Magnetic Resonance Imaging Maps Measures Membrane Microdialysis Modeling Movement Mus Pathology Pathway interactions Process Protein Isoforms Proteins Reporting Research Risk Factors Role Route Senile Plaques Sleep Symptoms System Tail Temporal Lobe Testing Textbooks Tg2576 Transfection Transgenic Mice Up-Regulation Variant Viral abeta accumulation abeta deposition age related aged aging brain amyloid formation aquaporin 4 base brain cell brain parenchyma brain tissue contrast enhanced extracellular frontal lobe glymphatic dysfunction glymphatic function glymphatic system human tissue in vivo interstitial mouse model novel therapeutic intervention overexpression prevent radiotracer solute tau Proteins wasting water channel young adult

项目摘要

Summary Abstract Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the formation of senile plaques, extracellular aggregates composed of the protein Aβ that begin forming more than a decade before the onset of clinical symptoms. Aging is the strongest risk factor for the development of AD, yet the factors that render the aging brain vulnerable to Aβ deposition remain unknown and no treatments exist that can prevent or reverse this process in the aging brain. We have recently defined a brain-wide perivascular network, termed the `glymphatic' system that facilitates the exchange of interstitial fluid and cerebrospinal fluid, facilitating the clearance of interstitial wastes including Aβ from the brain. Fluid movement along these pathways and through the brain interstitium is facilitated by the water channel aquaporin-4 (AQP4) which is expressed in a highly polarized manner in astrocyte membranes that directly face the brain vasculature. Genetic deletion of AQP4 slows Aβ clearance from the brain and accelerates Aβ plaque deposition in a transgenic mouse model of AD. We have observed that perivascular AQP4 localization is disrupted in both the aging mouse and human cortex, and that in the human cortex, loss of perivascular AQP4 localization is associated with worsening Aβ plaque burden and AD. Based on these findings, we propose that loss of perivascular AQP4 localization in the aging brain impairs interstitial Aβ clearance and promotes Aβ plaque formation. In this proposal, we will use a transgenic mouse model that lacks perivascular AQP4 localization to determine whether loss of AQP4 localization slows interstitial Aβ clearance. We will then use an in vivo viral transfection approach to test whether upregulation of the AQP4-M23 variant, which is upregulated in the aging brain, disrupts perivascular AQP4 localization and impairs glymphatic pathway function. These two approaches will then be used to determine whether loss of perivascular AQP4 localization, including by AQP4-M23 upregulation, promotes Aβ plaque deposition in a mouse model of AD that spontaneously develops Aβ plaques. Using MRI-based imaging of glymphatic function, we will evaluate whether regions of impaired glymphatic function promote local Aβ plaque deposition. If validated, then these studies may provide a mechanistic basis for the vulnerability of the aging brain to Aβ aggregation, including an explanation for the vulnerability of certain brain regions to this process early in the disease course. These findings may identify a new therapeutic approach to preventing these processes in the aging brain.

摘要阿尔茨海默氏病（AD）是全球痴呆的主要原因，其特征在于老年斑，由蛋白A β组成的细胞外聚集体，开始形成超过十年在临床症状出现之前。衰老是AD发展的最强风险因素，然而，使衰老大脑易受A β沉积影响的因素仍然未知，可以阻止或逆转大脑老化的过程。我们最近定义了一种脑血管周围的网络，称为"胶质淋巴"系统，促进间质液和脑脊液的交换，促进包括A β在内的间质废物从脑中清除。流体运动沿着这些水通道蛋白-4（AQP4）促进了脑内的钙通道，在直接面对脑血管的星形胶质细胞膜中以高度极化的方式表达。 AQP4基因缺失减缓A β从脑中清除并加速A β斑块沉积， AD的转基因小鼠模型。我们观察到血管周围AQP 4定位在两个组织中都被破坏衰老小鼠和人类皮质，以及在人类皮质中，血管周围AQP4定位的丧失是与A β斑块负荷恶化和AD相关。基于这些发现，我们建议，衰老脑血管周围AQP4定位损害间质A β清除并促进A β斑块阵在这个建议中，我们将使用一个缺乏血管周围AQP4定位的转基因小鼠模型，确定AQP4定位缺失是否减缓间质A β清除。然后我们将使用体内病毒转染方法，以测试AQP4-M23变体是否上调，其在衰老过程中上调脑，破坏血管周围AQP4定位并损害胶质淋巴通路功能。这两种方法然后将用于确定血管周围AQP4定位的丢失，包括AQP4-M23 在自发形成A β的AD小鼠模型中，斑块使用基于MRI的胶质淋巴功能成像，我们将评估受损区域是否胶质淋巴功能促进局部A β斑块沉积。如果得到验证，那么这些研究可以提供一个衰老大脑对A β聚集的脆弱性的机制基础，包括对在疾病过程的早期，某些大脑区域对这一过程的脆弱性。这些发现可能会发现一个新的治疗方法，以防止这些过程中老化的大脑。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A transcriptome-based assessment of the astrocytic dystrophin-associated complex in the developing human brain.

DOI：
10.1002/jnr.24082
发表时间：
2018-03
期刊：
Journal of neuroscience research
影响因子：
4.2
作者：
Simon MJ;Murchison C;Iliff JJ
通讯作者：
Iliff JJ

Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment.

DOI：
10.3389/fnagi.2021.788519
发表时间：
2021
期刊：
Frontiers in aging neuroscience
影响因子：
4.8
作者：
Li M;Kitamura A;Beverley J;Koudelka J;Duncombe J;Lennen R;Jansen MA;Marshall I;Platt B;Wiegand UK;Carare RO;Kalaria RN;Iliff JJ;Horsburgh K
通讯作者：
Horsburgh K

The Bidirectional Link Between Sleep Disturbances and Traumatic Brain Injury Symptoms: A Role for Glymphatic Dysfunction?