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：
10601099
负责人：
Li Gan
金额：
$ 83.41万
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/10601099
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 Inhibition Dementia Diet Disease Dose Electrophysiology (science)Exhibits Family Genes Genetic Genetic study Goals Hippocampus Human Genetics Hyperactivity Image Immune Immune response Immunomodulators Impairment Inflammation Inflammatory Response Innate Immune Response Interferon Activation Interferon Type I Interferons Intervention Late Onset Alzheimer Disease Learning Link Mediating Memory Loss Memory impairment Microglia Modeling Mus Neurofibrillary Tangles Neurons Nuclear Outcome Pathologic Pathology Pathway interactions Permeability Phenocopy Phosphorylation 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 Viral cell type clinical heterogeneity cognitive function cytokine ds-DNA hyperphosphorylated tau imaging study in vivo inhibitor mRNA Expression monocyte mouse model novel novel therapeutic intervention novel therapeutics pharmacokinetics and pharmacodynamics pharmacologic preclinical study protective effect recruit response risk variant sensor single nucleus RNA-sequencing small molecule tau Proteins tau mutation transcription factor transcriptome 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.

抽象的阿尔茨海默氏病（AD）是晚期痴呆症的最常见形式。 tau病理学的范围是与记忆下降密切相关。致病性TAU如何导致认知缺陷尚不清楚。虽然大多数关于TAU的研究一直集中在TAU对神经元的直接影响上，引人注目的人类遗传研究联系在一起适应不良的先天免疫反应，包括小胶质细胞反应，以提高迟到的风险阿尔茨海默氏病发作。先天免疫基因作为阿尔茨海默氏症的风险等位基因的惊人富集疾病支持不良适应性小胶质细胞在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毒性会导致新的治疗策略。在我们的初步研究，我们发现陶氏病小鼠表现出多活跃的GMP-AMP合酶（CGA） - 干扰素基因（STING）信号传导的刺激剂。作为胞质DNA的主要传感器，CGAS刺途径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类型I干扰素基因。自遗传降低以来在tau介导的空间学习和记忆缺陷的CGA中阿尔茨海默氏病。另外，保护效应与富含干扰素的减少有关小胶质细胞亚群和使用单一鉴定的疾病相关的小胶质细胞的重编程核RNA-seq。我们假设小胶质CGAS-sting过度激活介导了适应不良的 auopathy中增强疾病的小胶质细胞反应。为了检验这一假设，在AIM 1中，我们将首先确定小胶质细胞中的CGA激活如何增强TAU毒性（1a）。结合单核RNA-seq，病理和功能分析，我们将调查小胶质细胞中CGAS过度激活的毒性是骨髓来源的单核细胞（1B，1C）。在AIM 2中，我们将剖析CGA激活的毒性作用陶氏病是由依赖于刺激或独立的机制介导的，我们将确定是否损失 CHACOPIES CGA灭活对TAU毒性和转录组变化的影响（2a）。然后我们会通过评估CGAS灭活方式如何影响CGAS激活的无关刺激的机制 tau毒性在sting null背景（2b）上。 CGA部分损失的重大保护作用支持对CGA的药理抑制剂的部分抑制可能对tauopathy有益。我们证明了一个特定的CGA抑制剂TDI6570是大脑渗透的，有效抑制1型干扰素的表达 tauopathy小鼠中的靶基因。然后，我们将使用基于pk/pd的配方盘优化给药，然后评估CGA抑制剂在扭曲症中认知不足之前或之后的有益作用 AIM 3中的小鼠。拟议研究的完成将确定先天性的新型疾病增强特性 AD中的免疫反应，为药理学干预提供了新的治疗方向。