Maladaptive antiviral pathways in Alzheimer's disease

阿尔茨海默病的适应不良抗病毒途径

基本信息

批准号：
10424548
负责人：
Li Gan
金额：
$ 83.07万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10424548
关键词：
Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Antiviral Response Binding Bone Marrow Brain Cell Nucleus Cells Cognitive deficits Cyclic GMP DNA DNA Damage DNA Repair Dementia Diet Disease Dose Electrophysiology (science)Exhibits Family Genes Genetic Genetic study Goals Hippocampus (Brain)Human Genetics Hyperactivity Image Immune Immune response Immunomodulators Impairment Inflammatory Response Innate Immune Response Interferon Activation Interferon Type I Interferons Intervention Late Onset Alzheimer Disease Lead Learning Link Mediating Memory Memory Loss Memory impairment Messenger RNA Microglia Modeling Mus Neurofibrillary Tangles Neurons Nuclear Outcome Pathologic Pathology Pathway interactions Permeability Pharmacology Phenocopy Plasma Preventive Property Proteins Risk Role Senile Plaques Signal Transduction Source Stimulator of Interferon Genes Sting Injury Synapses TANK-binding kinase 1 Tauopathies Testing Therapeutic Toxic effect base cell type clinical heterogeneity cognitive function cytokine ds-DNA hyperphosphorylated tau imaging study in vivo inhibitor monocyte mouse model novel novel therapeutic intervention novel therapeutics pharmacokinetics and pharmacodynamics preclinical study protective effect recruit response risk variant sensor small molecule tau Proteins tau mutation transcription factor transcriptome transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Alzheimer's disease (AD) is the most common form of late-onset dementia. The extents of tau pathology are closely related to memory decline. How pathogenic tau causes cognitive deficits is not clear. While most studies on tau have been focused on direct effects of tau on neurons, compelling human genetic studies linked maladaptive innate immune responses, including microglial responses, to elevated risk of developing late- onset Alzheimer disease. The striking enrichment of innate immune genes as risk alleles for Alzheimer disease supports critical disease-enhancing role of maladaptive microglia in tau-mediated cognitive deficits. Identifying how maladaptive microglial enhances tau toxicity could lead to new therapeutic strategies. In our preliminary studies, we found that tauopathy mice exhibit hyperactive Cyclic GMP-AMP synthase (cGAS)- Stimulator of interferon genes (STING) signaling. As a major sensor of cytosolic DNA, cGAS-STING pathway mobilizes antiviral responses via activation of interferon regulatory factors (IRFs) and expression of cytokine and type I interferon genes. The hyperactive cGAS pathways contributes to tau toxicity since genetic reduction of cGAS protected against tau-mediated spatial learning and memory deficits in a tauopathy mouse model of Alzheimer disease. In addition, the protective effects were associated with reduced interferon-enriched microglial subpopulations and reprogramming of disease-associated microglial states as identified using single nuclei RNA-seq. We hypothesize that microglial cGAS-STING hyperactivation mediates the maladaptive disease-enhancing microglial response in tauopathy. To test this hypothesis, In Aim 1, we will first determine how cGAS activation in microglia enhances tau toxicity (1a). Using a combination of single nuclei RNA-seq, pathological and functional analyses, we will investigate if toxicity from cGAS hyperactivation in microglia or bone marrow-derived monocytes (1b, 1c). In Aim 2, we will dissect if the toxic effects of cGAS activation in tauopathy are mediated by STING-dependent or -independent mechanisms, we will determine if loss of STING phenocopies the effects of cGAS inactivation on tau toxicity and transcriptomic changes (2a). We will then determine STING-independent mechanisms of cGAS activation by assessing how cGAS inactivation affects tau toxicity on Sting null background (2b). The significant protective effects of partial loss of cGAS supports that partial inhibition with pharmacological inhibitors of cGAS could be beneficial for tauopathy. We showed that a specific cGAS inhibitor, TDI6570, is brain permeable and effectively inhibit expression of type 1 interferon target genes in tauopathy mice. We will then optimize the dosing using formulated chow based on PK/PD, and evaluate the beneficial effects of the cGAS inhibitor before or after the onset of cognitive deficit in tauopathy mice in Aim 3. Completion of the proposed study will identify novel disease-enhancing properties of innate immune responses in AD, and provide new therapeutic direction for pharmacological intervention.

抽象的阿尔茨海默病 (AD) 是最常见的迟发性痴呆症。 tau 病理学的范围是与记忆力衰退密切相关。致病性 tau 蛋白如何导致认知缺陷尚不清楚。虽然大多数对 tau 蛋白的研究主要集中在 tau 蛋白对神经元的直接影响，这与人类遗传学研究相关适应不良的先天免疫反应，包括小胶质细胞反应，导致发生晚期免疫反应的风险升高阿尔茨海默病发作。作为阿尔茨海默病风险等位基因的先天免疫基因显着富集疾病支持适应不良的小胶质细胞在 tau 介导的认知缺陷中的关键疾病增强作用。确定适应不良的小胶质细胞如何增强 tau 毒性可能会带来新的治疗策略。在我们的初步研究，我们发现 tau 蛋白病小鼠表现出过度活跃的环 GMP-AMP 合酶（cGAS）- 干扰素基因 (STING) 信号传导的刺激剂。作为细胞质 DNA 的主要传感器，cGAS-STING 通路通过激活干扰素调节因子 (IRF) 和细胞因子的表达来动员抗病毒反应和I型干扰素基因。由于基因减少，过度活跃的 cGAS 途径导致 tau 毒性 cGAS 可以保护 tau 蛋白病小鼠模型免受 tau 蛋白介导的空间学习和记忆缺陷阿尔茨海默病。此外，保护作用与富含干扰素的减少有关。使用单一方法确定的小胶质细胞亚群和与疾病相关的小胶质细胞状态的重编程细胞核 RNA 测序。我们假设小胶质细胞 cGAS-STING 过度激活介导了适应不良 tau蛋白病中小胶质细胞的疾病增强反应。为了检验这个假设，在目标 1 中，我们首先确定小胶质细胞中的 cGAS 激活如何增强 tau 毒性 (1a)。使用单核 RNA-seq 的组合，病理和功能分析，我们将研究小胶质细胞中 cGAS 过度激活是否会产生毒性或骨髓来源的单核细胞 (1b, 1c)。在目标 2 中，我们将剖析 cGAS 激活是否会产生毒性作用 tau蛋白病是由STING依赖性或独立机制介导的，我们将确定STING是否丢失表型复制 cGAS 失活对 tau 毒性和转录组变化的影响 (2a)。我们随后将通过评估 cGAS 失活如何影响，确定 cGAS 激活的 STING 独立机制 tau 对 Sting 无效背景的毒性 (2b)。 cGAS 部分丧失的显着保护作用支持这一点使用 cGAS 药物抑制剂进行部分抑制可能有益于 tau 蛋白病。我们证明了一个特异性cGAS抑制剂TDI6570具有脑渗透性，可有效抑制1型干扰素的表达 tau蛋白病小鼠的靶基因。然后，我们将根据 PK/PD 使用配方饲料优化剂量，并且评估 tau 蛋白病认知缺陷发生之前或之后 cGAS 抑制剂的有益作用目标 3 中的小鼠。完成拟议的研究将确定先天性的新的疾病增强特性 AD中的免疫反应，为药物干预提供新的治疗方向。