Role of apoE-mediated meningeal lymphatic remodeling in the pathophysiology of Alzheimer’s disease

apoE 介导的脑膜淋巴重塑在阿尔茨海默病病理生理学中的作用

基本信息

批准号：
10734287
负责人：
Sandro Da Mesquita
金额：
$ 225.07万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734287
关键词：
Abeta clearance Ablation Adult Affect Age Age Months Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Amyloidosis Apolipoprotein E Behavior Behavioral Blood Vessels Brain Brain Drains Cells Cerebrospinal Fluid Cervical lymph node group Cognition Cognitive Data Dependovirus Disease Drainage procedure Dura Mater Environment Female Flow Cytometry Functional disorder Future Gene Expression Profile Genes Genetic Genetic Carriers Gliosis Growth Factor Hippocampus Human Immune Immune system Impaired cognition Impairment Intercellular Fluid Knock-in Knock-in Mouse Knockout Mice Late Onset Alzheimer Disease Lead Link Liquid substance Lymph Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic function Macrophage Measures Mediating Memory impairment Meningeal Meningeal lymphatic system Microdialysis Microglia Molecular Morphology Mus Myelogenous Myeloid Cells Neurodegenerative Disorders Neurons Outcome Pathogenesis Performance Peripheral Phenotype Physiological Proteins Public Health Publications Reporting Risk Rodent Role Signal Transduction Synapses Synaptic plasticity Techniques Testing Therapeutic Tissues Tracer Vascular Endothelial Growth Factor C Vascular System abeta accumulation abeta deposition aged apolipoprotein E-3 apolipoprotein E-4 beta amyloid pathology brain dysfunction cerebral amyloidosis cognitive function cognitive performance conditional knockout cytokine glial activation high risk humanized mouse immune activation improved in vivo in vivo imaging interest lymphatic drainage lymphatic dysfunction lymphatic malformations lymphatic vasculature lymphatic vessel male middle age mouse model neuroinflammation novel novel therapeutics protein aggregation proteomic signature risk variant sex single-cell RNA sequencing source localization spatial memory therapy outcome transcriptome

项目摘要

ABSTRACT Aging and expression of apolipoprotein E ε4 (APOE4) gene alleles represent two major risk factors for Alzheimer’s disease. Recent studies have shown that aging leads to impaired brain fluid drainage by the bona fide lymphatic vascular network that is found in the mammalian meningeal dura. Interestingly, early loss of meningeal lymphatic drainage has been linked to worse amyloid-β (Aβ) pathology, vascular and microglial activation, and spatial memory deficits in Alzheimer’s disease mouse models of brain amyloidosis. However, little is known about the effects of APOE4 expression on meningeal lymphatic function. Our preliminary data shows that expression of APOE4 in humanized knock-in mice leads to a deleterious remodeling of meningeal lymphatic vessels and reduced drainage of cerebrospinal fluid (CSF) into the cervical lymph nodes. Interestingly, we also show that meningeal peri-lymphatic myeloid cells are a main local source of apoE protein and become activated in middle-aged APOE4 mice. These observations led us to raise the overarching hypothesis that expression of APOE4 disturbs the crosstalk between meningeal innate myeloid and lymphatic endothelial cells, which will subsequently lead to reduced CSF drainage by meningeal lymphatics, and exacerbated neuroinflammation and brain amyloidosis in Alzheimer’s disease. In Aim 1, we plan to use constitutive or conditional knockout mouse models to investigate the cell autonomous and non-autonomous effects of APOE4 on meningeal lymphatic dysfunction at different ages, determine the underlying innate immune transcriptional signatures, and identify alterations in lymphatic growth factors and/or cytokines. In Aim 2, we will test the hypothesis that an early impairment in meningeal lymphatic drainage promotes a faster cognitive decay in APOE4 mice, and that fine-tuning meningeal lymphatics in aged APOE4 mice ameliorates neuronal function and cognition in sex-dependent manner. To assess this, will modulate meningeal lymphatic drainage, using adeno- associated viruses that promote lymphatic vessel ablation or expansion, and evaluate the downstream effects on the neuronal transcriptomes, synaptic plasticity, and behavioral performances of aged female and male APOE humanized mice. In Aim 3, the therapeutic outcomes of manipulating meningeal lymphatic function will be tested in a knock-in Alzheimer’s disease mouse model of brain amyloidosis, the APP-SAA, expressing APOE3 or APOE4. After inducing meningeal lymphatic vessel loss or expansion in 2- and 10-month-old mice, we will evaluate different experimental outcomes including behavioral performance, neuronal activity, brain interstitial fluid Aβ (by in vivo microdialysis), soluble and insoluble Aβ aggregates, and the profiles of innate and adaptive immune cell activation in the brain and its border tissues. Altogether, this proposal will allow us to uncover novel mechanisms of meningeal lymphatic decline that will serve as cornerstones for future projects and might lead to novel therapies to treat APOE4 allele carriers that are at a greater risk of developing Alzheimer’s disease.

抽象的载脂蛋白Eε4（APOE4）基因等位基因的衰老和表达代表了两个主要风险因素阿尔茨海默氏病。最近的研究表明，衰老会导致BONA脑流体流失受损在哺乳动物脑膜硬脑膜中发现的FIDE淋巴血管网络。有趣的是，早期损失脑膜淋巴引流已与恶化的淀粉样蛋白β（Aβ）病理，血管和小胶质细胞有关激活，空间记忆在阿尔茨海默氏病小鼠脑淀粉样变性的小鼠模型中定义。然而，关于APOE4表达对脑膜淋巴功能的影响知之甚少。我们的初步数据表明在人源化的敲入小鼠中apoE4的表达导致脑膜的有害重塑淋巴管和脑脊液（CSF）排水减少到宫颈淋巴结中。有趣的是，我们还表明，脑膜淋巴周围的髓样细胞是APOE蛋白的主要局部来源，并成为在中年APOE4小鼠中激活。这些观察结果使我们提出了总体假设 APOE4的表达打扰了脑膜固有髓样和淋巴内皮细胞之间的串扰，随后，这将导致脑膜淋巴液减少CSF的排水，并加剧阿尔茨海默氏病的神经炎症和脑淀粉样变性。在AIM 1中，我们计划使用本构或有条件的敲除小鼠模型，以研究APOE4的细胞自主和非自主效应在不同年龄的脑膜淋巴功能障碍上，确定基本的先天免疫转录签名并确定淋巴生长因子和/或细胞因子的改变。在AIM 2中，我们将测试假设脑膜淋巴引流的早期损害会促进更快的认知衰减 APOE4小鼠，以及老年APOE4小鼠的微调脑膜淋巴细胞来改善神经元功能和以性别依赖性的方式认知。为了评估这一点，将使用腺促进淋巴管消融或膨胀的相关病毒，并评估下游效应在神经元的转录组，突触可塑性和老年雌性ApoE的行为表现上人源化的小鼠。在AIM 3中，将测试操纵脑膜淋巴功能的治疗结果在脑淀粉样变性的阿尔茨海默氏病小鼠模型中，App-SAA表达APOE3或 APOE4。在2个月大的小鼠和10个月大的小鼠中诱导脑膜淋巴管损失或膨胀后，我们将评估不同的实验结果，包括行为表现，神经元活动，脑间隙流体Aβ（通过体内微透析），可溶性和不溶于Aβ聚集体以及先天和适应性的曲线大脑及其边界组织中的免疫细胞活化。总之，该提议将使我们能够发现小说脑膜淋巴下降的机制将成为未来项目的基石，并可能导致治疗APOE4等位基因携带者的新型疗法，该载体患阿尔茨海默氏病的风险更大。