Peripheral TGF-beta Pathway Inhibitor Therapy in Alzheimer's Rats

阿尔茨海默病大鼠的外周 TGF-β 通路抑制剂治疗

• 批准号: 10192843
• 负责人: KAREN T CHANG
• 金额: $ 60.72万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192843
• 关键词: 3-Dimensional; Abeta clearance; Address; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; American; Amyloid; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Animal Disease Models; Astrocytes; Attention; Attenuated; Biochemical; Blood; Brain; Brain imaging; Brain scan; Cell Death; Cells; Cerebrum; Chronic; Coupled; Coupling; Cross-Sectional Studies; Data; Dichloromethylene Diphosphonate; Diffusion; Disease; Disease Progression; Encephalitis; Event; Evolution; Genetic; Hematogenous; Histologic; Homeostasis; Human; Hybrids; Image; Imaging technology; Immune; Immunity; Immunosuppression; Impaired cognition; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Investigational Therapies; Kinetics; Learning; Licensing; Liposomes; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mediating; Memory; Messenger RNA; Microglia; Modeling; Multimodal Imaging; Names; Natural Immunity; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Injury; Non-Steroidal Anti-Inflammatory Agents; Pathologic; Pathology; Pathway interactions; Peripheral; Phagocytosis; Pharmacology; Plasma; Primary Prevention; Publishing; Rattus; Scanning; Senile Plaques; Signal Transduction; Structural defect; Structure; Study models; Supporting Cell; Testing; Time; Tracer; Transforming Growth Factor beta; Transgenic Organisms; Ursidae Family; Work; abeta deposition; behavior test; brain cell; cerebral amyloidosis; cognitive function; cognitive testing; cohort; cytokine; design; effective therapy; experimental study; genome wide association study; imaging approach; in silico; inhibitor/antagonist; macrophage; microPET; mind control; multimodality; mutant; nanoparticle; neuroinflammation; neuron loss; novel; pre-clinical; preempt; presenilin-1; prevent; relating to nervous system; risk variant; serial imaging; small molecule; tau Proteins; therapeutically effective; tractography

PROJECT SUMMARY While amyloid plaques and neurofibrillary tangles are Alzheimer's disease (AD) defining features, Alzheimer himself originally identified a third pathology– inflammation of the brain's glial support cells. Neuroinflammation in AD is characterized by reactive astrocytes and microglia that surround amyloid plaques and chronically secrete inflammatory innate immune cytokines. The dominant view for decades has been that all forms of inflammation damage the AD brain. Yet, non-steroidal anti-inflammatory drugs failed to produce a positive signal for AD primary prevention. This raises a fundamental question: should we be blocking or possibly even promoting inflammation as an AD therapeutic? While the focus has mainly been on pro-inflammatory cerebral innate immunity, little attention has been paid to factors that curtail peripheral innate immune responses. The unifying theme of our work is that `rebalancing' peripheral innate immunity to homeostasis by releasing immunosuppression will limit AD progression. Strikingly, our focus on innate immunity in AD has just recently been validated by genome-wide association studies. These results have taken the field by storm; identifying clusters of AD risk alleles in core peripheral macrophage pathways. As a key cytokine suppressor of innate immunity and inflammation, transforming growth factor-beta (TGF-β) mRNA abundance is increased in AD patient brains. We hypothesize that the AD brain over- compensates to pro-inflammatory signals by producing these abnormally high levels of TGF-β. Paradoxically, this sets up early, low-level and chronic neuroinflammation that fails to support amyloid-β (Aβ) clearance. I and my team have shown in published and preliminary data that genetic or pharmacologic blockade of TGF-β- Smad 2/3 signaling in peripheral macrophages leads to brain entry of these cells and Aβ phagocytosis; sparing neurons from injury and restoring learning and memory. To further explore this theme, we have now generated the TgF344-AD rat that recapitulates cognitive impairment and the full array of human AD pathological features: neuroinflammation, plaques, tangles, and frank neuronal loss. In AIM 1, we will use non-invasive longitudinal imaging approaches to determine whether early neuroinflammation preempts later cognitive impairment, Aβ deposition, structural connectivity changes and neuronal death in TgF344-AD rats. AIM 2 is designed to longitudinally evaluate if blocking peripheral innate immune TGF-β signaling licenses Aβ phagocytosis and mitigates AD-like changes by delivering cutting- edge nanoparticles containing small molecule TGF-β-Smad 2/3 signaling inhibitor payload to hematogenous macrophages. Finally, we will pharmacologically delete peripheral macrophages to definitively establish if they are responsible for the beneficial effects of TGF-β signaling inhibition. While AD animal model studies are typically limited by cross-sectional designs, this project will break this barrier by coupling the most advanced multimodal, longitudinal brain imaging with peripheral TGF-β signaling inhibition in the TgF344-AD rat.

项目摘要 淀粉样蛋白斑块和神经原纤维缠结是阿尔茨海默氏病（AD）定义特征，但 阿尔茨海默氏症本人最初确定了大脑神经胶质支持细胞的第三个病理 - 炎症。 AD中的神经炎症的特征是反应性星形胶质细胞和小胶质细胞周围淀粉样蛋白斑块 并长期分泌炎症性的先天免疫细胞因子。几十年来的主要观点是 各种形式的炎症会损害广告大脑。然而，非甾体类抗炎药未能产生 广告初级预防的正信号。这就提出了一个基本问题：我们应该阻止还是可能 甚至促进炎症作为广告疗法？虽然重点主要用于促炎 大脑先天免疫，很少关注减少外围先天免疫力的因素 回答。我们作品的统一主题是，“重新平衡”周围的天生对体内平衡的免疫力 释放免疫抑制将限制AD进展。令人惊讶的是，我们专注于AD中的先天免疫力 最近通过全基因组关联研究来验证。这些结果席卷了现场。 识别核心外围巨噬细胞途径中的AD风险等位基因簇。 作为先天免疫和注射的关键细胞因子抑制剂，转化生长因子β （TGF-β）AD患者大脑中的mRNA丰度增加。我们假设广告大脑过度 通过产生这些绝对高水平的TGF-β来补偿促炎信号。矛盾的是， 这使早期，低水平和慢性神经炎症无法支持淀粉样蛋白β（Aβ）清除率。我 我的团队在已发布和初步数据中显示了TGF-β-的遗传或药物阻滞 周围巨噬细胞中的SMAD 2/3信号传导导致这些细胞的大脑进入和Aβ吞噬作用。保留 受伤并恢复学习和记忆的神经元。 为了进一步探索这个主题，我们现在生成了概括认知的TGF344-AD老鼠 损害和全部人类AD病理特征：神经炎症，斑块，缠结和 弗兰克神经元损失。在AIM 1中，我们将使用非侵入性纵向成像方法来确定是否是否 早期的神经炎症促进了后来的认知障碍，Aβ沉积，结构连通性的变化 TGF344-AD大鼠的神经元死亡。 AIM 2旨在纵向评估是否阻塞周围 先天免疫TGF-β信号传导许可Aβ吞噬作用，并通过提供切割来减轻AD样变化 含有小分子TGF-β-SMAD 2/3信号抑制剂有效载荷的边缘纳米颗粒对血源性 巨噬细胞。最后，我们将实际删除外围巨噬细胞，以确定它们是否是否 负责TGF-β信号抑制的有益作用。而广告动物模型研究是 通常受横截面设计的限制，该项目将通过耦合最先进的 TGF344-AD大鼠中周围TGF-β信号传导抑制多模式的纵向脑成像。

项目成果

MyD88 is dispensable for cerebral amyloidosis and neuroinflammation in APP/PS1 transgenic mice.

• DOI: 10.1016/j.ajpath.2014.07.004
• 发表时间: 2014-11
• 期刊: The American journal of pathology
• 作者: T. Weitz;D. Gate;K. Rezai-zadeh;T. Town

Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer's Disease Pathogenesis.

• DOI: 10.3233/jad-170887
• 发表时间: 2018
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Meyer PF;Savard M;Poirier J;Labonté A;Rosa-Neto P;Weitz TM;Town T;Breitner J;Alzheimer’s Disease Neuroimaging Initiative;PREVENT-AD Research Group
• 通讯作者: PREVENT-AD Research Group

Innate Immunity Fights Alzheimer's Disease.

• DOI: 10.1016/j.tins.2015.08.008
• 发表时间: 2015-11
• 期刊: Trends in neurosciences
• 影响因子: 15.9
• 作者: Guillot-Sestier MV;Doty KR;Town T
• 通讯作者: Town T