Microglial lysosomes and selective neuronal vulnerability

小胶质细胞溶酶体和选择性神经元脆弱性

基本信息

批准号：
10599106
负责人：
Lindsay Mitchell De Biase
金额：
$ 39.75万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599106
关键词：
Affect Age Aging Autophagocytosis Basal Ganglia Behavior Brain region CLN3 gene Calcium Cell Nucleus Cell Shape Cell physiology Cells Chemosensitization Code Cognition Data Degenerative Disorder Depressed mood Electrophysiology (science)Excitatory Synapse Exhibits Face Functional disorder Gene Expression Genes Goals Health Homeostasis Image Impaired cognition Impairment Inflammation Inflammatory Knockout Mice Link Lipids Lipofuscin Location Longevity Lysosomes Macrophage Maps Measures Membrane Methods Microglia Molecular Molecular Target Movement Mus Neurodegenerative Disorders Neuroglia Neurons Neurosciences Nucleus Accumbens Organelles Parkinsonian Disorders Pathway interactions Peptide Hydrolases Phagocytes Phagocytosis Phenotype Play Population Positioning Attribute Process Production Proliferating Property Proteins Proton Pump Recycling Regulation Risk Role Shapes Signal Transduction Slice Substantia nigra structure Symptoms Synapses Synaptic plasticity Testing Variant Ventral Tegmental Area Vulnerable Populations Work age related cell motility cognitive function confocal imaging density dopaminergic neuron experimental study follow-up functional decline functional status in vivo interdisciplinary approach lysosome membrane middle age neuroprotection novel novel strategies overexpression pars compacta preservation receptor regional difference response single-cell RNA sequencing synaptic function synaptogenesis tissue fixing transcriptome sequencing virtual young adult

项目摘要

Project Summary / Abstract The overall goal of this proposal is to reveal central regulators of microglial attributes that can impact synapses. Synaptic dysfunction is tightly linked to declining cognition and neuronal health during aging. A long- standing mystery in neuroscience is why some CNS neurons are more vulnerable to age-associated synapse loss and neurodegenerative disease. Microglia are well-positioned to influence synapses throughout the lifespan, being equipped to induce synapse formation, synapse elimination and alter synapse composition through multiple mechanisms. Moreover, synapse-relevant attributes of microglia change during aging, including their cell process motility, phagocytic behaviors, and production of inflammatory factors. We and others recently discovered that microglia exhibit region-specific phenotypes, raising the possibility that microglial regulation of synaptic health varies. In addition, our preliminary data indicate that ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) microglia begin to proliferate and produce inflammatory factors during midlife in mice, and months before microglia in other basal ganglia nuclei. These “pockets” of early inflammation are likely detrimental to synaptic function of nearby dopamine neurons, which are highly vulnerable to functional decline and degenerative disease during aging. Here, we will investigate the possibility that microglial lysosomes can simultaneously regulate multiple synapse-relevant attributes of these cells, and that regional differences in lysosome function give rise to regional variation in microglial aging and synapse vulnerability. Lysosomes are typically viewed as purely degradative organelles, but new data show that they are intimately involved in membrane recycling and intracellular signaling that can shape cell properties. Indeed, lysosomes play a central role in regulating macrophage phenotype, including their inflammatory profiles, phagocytosis, and responses to aging. Our findings suggest that lysosomes play similar regulatory roles within microglia; the region-specific phenotypes and responses to aging that we observe within VTA/SNc microglia were accompanied by prominent differences in lysosome abundance, expression of lysosome component genes, and rates of lysosome overload with protein-lipid aggregates, compared to microglia in other basal ganglia nuclei. Nonetheless, surprising little is known about microglial lysosomes in vivo. Focusing on the basal ganglia and working in mice, we will use multidisciplinary approaches to define the composition and functional status of microglial lysosomes across brain regions and lifespan (Aim 1). We developed novel methods to manipulate microglial lysosome overload and will determine how this shapes synapse-relevant microglial attributes during aging (Aim 2). Finally, we will directly measure how microglial lysosome overload affects lifespan synaptic integrity and function in distinct brain regions (Aim 3). These studies will reveal whether these organelles are central orchestrators of microglial phenotype and will identify molecular targets for promoting neuroprotective microglial phenotypes to preserve synaptic function in vulnerable populations of neurons.

项目摘要 /摘要该提案的总体目标是揭示可能影响的小胶质属性的中央监管机构突触。突触功能障碍与衰老过程中认知和神经元健康的下降紧密相关。沿着- 神经科学中的神秘状态是为什么某些CNS神经元更容易受到年龄相关的突触的原因丧失和神经退行性疾病。小胶质细胞良好地影响整个过程中的突触寿命，等同于诱导突触形成，消除突触和改变突触组成通过多种机制。此外，衰老期间小胶质细胞变化的突触相关属性，包括它们的细胞过程运动，吞噬行为和炎症因素的产生。我们和其他人最近发现，小胶质细胞暴露于区域特异性表型，这增加了这样的可能性突触健康的小胶质调节。此外，我们的初步数据表明腹侧换侧段面积（VTA）和黑质Nigra Pars Compacta（SNC）小胶质细胞开始增殖并产生炎症小鼠中年的因素，以及其他基底神经节核中小胶质细胞之前的几个月。这些“口袋” 早期炎症可能会损害近多巴胺神经元的突触功能，这是高度的衰老期间容易受到功能下降和退化性疾病的影响。在这里，我们将调查可能性小胶质细胞溶酶体可以轻松调节这些细胞的多个与突触相关的属性，并且溶酶体功能的区域差异导致小胶质老化和突触的区域变化脆弱性。溶酶体通常被视为纯粹的降解细胞器，但新数据表明它们密切参与可以塑造细胞特性的膜回收和细胞内信号传导。的确，溶酶体在调节巨噬细胞表型中起着核心作用，包括其炎症特征，吞噬作用和对衰老的反应。我们的发现表明，溶酶体在小胶质细胞；我们在VTA/SNC小胶质细胞中观察到的特定区域的表型和对衰老的反应通过溶酶体抽象的显着差异，溶酶体成分的表达来实现与其他碱性的小胶质细胞相比神经节核。但是，对于体内的小胶质细胞溶酶体知之甚少。专注于基本神经节和在小鼠中工作，我们将使用多学科的方法来定义组成和功能跨大脑区域和寿命的小胶质溶酶体的状态（AIM 1）。我们开发了新颖的方法操纵小胶质细胞溶酶体过载，并将确定这种形状与突触相关的小胶质细胞衰老期间的属性（AIM 2）。最后，我们将直接测量小胶质溶酶体过载如何影响寿命突触完整性和在不同大脑区域的功能（AIM 3）。这些研究将揭示这些研究是否细胞器是小胶质表型的中心编排，将确定促进的分子靶标神经保护型小胶质细胞表型，以保留脆弱神经元种群的突触功能。