Microglial regulation of neuronal activity in TDP-43 neurodegeneration

TDP-43 神经变性中神经元活动的小胶质细胞调节

基本信息

批准号：
10667234
负责人：
Long-Jun Wu
金额：
$ 218.82万
依托单位：
MAYO CLINIC ROCHESTER
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：
2023-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667234
关键词：
Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Cells Central Nervous System Characteristics Chronic DNA-Binding Proteins Dendrites Dependence Disease Disease Progression Electron Microscopy Frontotemporal Dementia Gene Expression Genetic Genetic Induction Heterogeneity Hyperactivity Immune Microglia Modeling Mus Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Neurons Patients Phase Process Proliferating Recovery Regulation Reporting Rod Role Shapes Signal Transduction Synapses Testing awake frontotemporal lobar dementia amyotrophic lateral sclerosis genetic approach glial activation imaging modality improved in vivo two-photon imaging innovation insight mouse model neuronal circuitry neuroprotection neurotransmission novel protein TDP-43 protein aggregation receptor response spatiotemporal targeted treatment therapeutic target two-photon

项目摘要

PROJECT SUMMARY Microglia, as the resident immune cells of the central nervous system, are key players in aging and neurodegenerative diseases, such as Alzheimer’s disease (AD) and AD-related dementias (ADRD). However, how microglia sense and regulate neurodegeneration remains largely unknown. TDP-43 is a DNA-binding protein that is a main component of the protein aggregates found in amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD), and AD. We used inducible mouse model of TDP-43 translocation (rNLS8) that can mimic characteristic features of TDP-43 related neurodegeneration. Utilizing in vivo two- photon imaging, we have demonstrated that rNLS8 mice show neuronal hyperactivity in the cortex during disease progression, which is associated with unique rod-shaped microglia aligning along neuronal dendrites in the layer 4 cortex. Based on these exciting observations, we hypothesize that microglia have neuroprotective roles by regulating cortical microcircuit and attenuating neuronal hyperactivity in response to TDP-43 related neurodegeneration. We will test this hypothesis with the following three Aims: Aim 1: Determine the functional heterogeneity of microglial activation in TDP-43 neurodegeneration. We will use chronic, in vivo two-photon imaging to determine the spatiotemporal activation of microglia, including process dynamics, landscape changes, and proliferation. In addition, we will examine microglial Ca2+ activity using a newly developed microglial GCaMP7s mouse line and TREM2 dependence. The results from this aim will uncover microglial heterogeneity in different phases of TDP-43 related neurodegeneration. Aim 2: Investigate how microglia regulate cortical microcircuits in TDP-43 neurodegeneration. We will study microglia-neuron interactions in different cortical layers during disease progression and recovery in rNLS8 mice using simultaneous two-photon and electron microscopy. We will also determine how microglial TREM2 regulates neuronal circuits, particularly during the early phases of disease progress, in TDP-43 related neurodegeneration. Aim 3: Manipulate microglia as a potential therapeutic target in TDP-43 neurodegeneration. We will precisely control microglial function using chemogenetics in the different phases of disease and delineate microglial contributions. In addition, we will target TREM2 for treatment of TDP-43 related neurodegeneration. Our group is perfectly poised to exploit novel methods of imaging microglia-neuron interactions and study their precise function in aging and TDP-43 related neurodegeneration like ALS, FTLD and AD. These innovative approaches will provide transformative insights into microglial mechanisms of regulating TDP-43 related neurodegeneration and spawn putative therapeutic targets that will ultimately help patients with ALS, FTLD, AD, and ADRD.

项目概要小胶质细胞作为中枢神经系统的常驻免疫细胞，在衰老和衰老过程中发挥着关键作用。神经退行性疾病，例如阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD)。小胶质细胞如何感知和调节神经退行性变仍然很大程度上未知。蛋白质是肌萎缩侧索硬化症 (ALS) 中蛋白质聚集体的主要成分，额颞叶痴呆 (FTLD) 和 AD 我们使用 TDP-43 易位的诱导小鼠模型。 (rNLS8) 可以利用体内二元模拟 TDP-43 相关神经变性的特征。光子成像，我们已经证明 rNLS8 小鼠在皮层中表现出神经过度活跃疾病进展，与沿神经元树突排列的独特杆状小胶质细胞有关基于这些令人兴奋的观察，我们发现小胶质细胞在第 4 层皮质中具有通过调节皮质微电路和减弱神经元过度活跃来发挥神经保护作用我们将通过以下三个目标来检验这一假设：目标 1：确定 TDP-43 神经变性中小胶质细胞激活的功能异质性。我们将使用慢性体内双光子成像来确定小胶质细胞的时空激活，包括过程动力学、景观变化和增殖。此外，我们将检查小胶质细胞 Ca2+。使用新开发的小胶质细胞 GCaMP7s 小鼠系的活性和 TREM2 依赖性的结果。这一目标将揭示 TDP-43 相关神经变性不同阶段的小胶质细胞异质性。目标 2：研究小胶质细胞如何调节 TDP-43 神经变性中的皮质微电路。研究疾病进展和恢复过程中不同皮质层的小胶质细胞-神经元相互作用我们还将使用同步双光子和电子显微镜来确定 rNLS8 小鼠的小胶质细胞。 TREM2 在 TDP-43 相关疾病中调节神经回路，特别是在疾病进展的早期阶段神经变性。目标 3：将小胶质细胞作为 TDP-43 神经变性的潜在治疗靶点。利用化学遗传学在疾病的不同阶段精确控制小胶质细胞功能并描绘此外，我们将针对 TREM2 来治疗 TDP-43 相关的神经变性。我们的小组完全准备好开发小胶质细胞-神经元相互作用成像的新方法并研究它们衰老和 TDP-43 相关神经退行性疾病（如 ALS、FTLD 和 AD）的精确功能。方法将为调节 TDP-43 相关的小胶质细胞机制提供变革性的见解神经退行性变并产生假定的治疗靶点，最终将帮助患有 ALS、FTLD 的患者， AD 和 ADRD。