Maladaptive antiviral pathways in Alzheimer's disease

摘要 阿尔茨海默病(AD)是最常见的迟发性痴呆。Tau的病理范围是 与记忆力衰退密切相关。致病性tau是如何导致认知缺陷的尚不清楚。虽然大多数人 关于tau的研究一直集中在tau对神经元的直接影响上，这使得人类遗传学研究与 适应不良的先天免疫反应，包括小胶质细胞反应，以增加晚期发展的风险- 起病的阿尔茨海默病。阿尔茨海默病危险等位基因先天免疫基因的显著丰富 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毒性可能导致新的治疗策略。在我们的 初步研究发现，自闭症小鼠表现出高活性的环状GMP-AMP合成酶(CGAS)- 干扰素基因刺激物(STING)信号。作为胞质DNA的主要感受器，cGAS-STING途径 通过激活干扰素调节因子和表达细胞因子来动员抗病毒反应 和I型干扰素基因。由于基因减少，过度活跃的cGAS途径参与了tau的毒性作用。 CGAS对tau介导的空间学习和记忆障碍的保护作用 阿尔茨海默病。此外，保护作用与减少干扰素含量有关。 小胶质细胞亚群和疾病相关小胶质细胞状态的重编程 核糖核酸序列。我们假设小胶质细胞cGAS刺激性过度激活介导了适应不良 肌萎缩侧索硬化症的疾病增强型小胶质细胞反应。为了检验这一假设，在目标1中，我们将首先确定 小胶质细胞中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，我们将调查cGAS过度激活对小胶质细胞或 骨髓来源的单核细胞(1b、1c)。在目标2中，我们将剖析cGAS激活在 相互作用是由刺依赖或非独立的机制介导的，我们将确定刺的丢失 研究了cGAS失活对tau毒性和转录改变的影响(2a)。到时候我们会的 通过评估cGAS失活如何影响确定cGAS激活的非刺激性机制 Tau对Sting零本底的毒性(2b)。CGAS部分丧失的显著保护作用支持 部分抑制cGAS的药理作用可能有利于治疗肌萎缩侧索硬化。我们展示了一个 特异性cGAS抑制剂TDI6570是大脑通透性的，并有效地抑制1型干扰素的表达 多动症小鼠的靶基因。然后我们将使用基于PK/PD的配方食物来优化剂量，并且 评估cGAS抑制剂在颈椎病认知功能障碍发作前后的益处 目标3.拟议研究的完成将确定先天的新的致病特性 阿尔茨海默病的免疫反应，为药物干预提供新的治疗方向。

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.