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: 8221480
• 负责人: TERRENCE C TOWN
• 金额: $ 36.53万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8221480
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid; Amyloid beta-Protein Precursor; Amyloidosis; Animal Model; Automobile Driving; Behavioral; Blood; Brain; Cell surface; Cells; Cerebrum; Data; Dementia; Deposition; Development; Dichloromethylene Diphosphonate; Disease; Disease Progression; Elderly; Encapsulated; Encephalitis; Equilibrium; Genetic; Gliosis; Goals; Hematogenous; Human; Image; Immune; Impaired cognition; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-10; Kinetics; Learning; Liposomes; Measures; Memory; Messenger RNA; Modeling; Mononuclear; Mus; Mutation; Neurofibrillary Tangles; Neuroglia; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Phagocytes; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Primary Prevention; Public Health; Publishing; Rattus; Research; Senile Plaques; Signal Transduction; Tauopathies; Testing; Tg2576; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Transgenes; Transgenic Mice; Transgenic Organisms; Work; age related; aged; base; brain cell; cytokine; early onset; familial Alzheimer disease; inhibitor/antagonist; killings; macrophage; mouse model; mutant; neuroinflammation; neuron loss; neuropathology; next generation; novel; novel therapeutic intervention; peripheral blood; presenilin-1; prevent; progressive neurodegeneration; small molecule; theories

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common dementia, and is hallmarked by deposition of A¿ peptides as 'senile' ¿-amyloid plaques, neuropathology, and neuroinflammation. Brain inflammation ultimately fails at mitigating AD pathology. However, broadly inhibiting inflammation has not produced a positive signal for AD primary prevention. This and other evidence has prompted our overarching hypothesis: that re-balancing inflammation as opposed to shutting it off completely may be beneficial for AD. The cardinal suppressive cytokine transforming growth factor-¿ (TGF-¿) keeps overly exuberant inflammation in check to guard against bystander tissue injury. Others have demonstrated that TGF-¿1 mRNA is ~3-fold higher in AD patient brains vs. healthy elderly controls, potentially biasing toward a suppressive milieu that is ineffective at restricting cerebral amyloidosis. Our published and preliminary data using genetic and pharmacologic approaches in mouse models of cerebral amyloidosis suggest that re-balancing (by inhibiting) TGF-¿ signaling in hematogenous mononuclear phagocytes promotes their brain infiltration and A¿/¿-amyloid clearance. We have developed a working hypothesis that re-balancing TGF-¿ signaling may restrict AD-like pathology. A key limitation to fully testing this hypothesis has been unavailability of an animal model that faithfully recapitulates human AD. To overcome this, we have developed a novel rat model of AD (line TgF344-AD) based on co-expression of mutant human amyloid precursor protein and presenilin-1, each independent causes of early-onset familial AD. Strikingly, TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes gliosis, tauopathy, neuronal loss and cognitive disturbance. Unlike A¿-driven transgenic mice, which model cerebral amyloid well but not the full spectrum of AD pathologies, these transgenic rats develop progressive neurodegeneration of the Alzheimer type. This next-generation AD rat model will enable basic and translational AD research, and offers a unique opportunity to evaluate the 'amyloid cascade hypothesis' of AD. The overarching goal of this proposal is to utilize TgF344-AD rats to evaluate whether pharmacologic inhibition of peripheral TGF-¿ signaling mobilizes hematogenous A¿ mononuclear phagocytes to restrict AD- like pathology. The focus of Specific Aim 1 will be to assess whether peripheral blockade of TGF-¿-Smad 2/3 signaling prevents or slows cerebral amyloidosis leading to neuropathology and cognitive decline. In Specific Aim 2, we will determine if peripheral TGF-¿-Smad 2/3 pathway inhibition treats established Alzheimer-type disease and reduces cognitive impairment. Specific Aim 3 will evaluate whether beneficial effects of peripheral TGF-¿ signaling blockade in transgenic Alzheimer rats are macrophage-dependent. Our hypotheses in this aim are two-fold: 1) that peripheral TGF-¿ signaling inhibition will promote brain infiltration of hematogenous A2 phagocytes with an 'alternate M2' activation profile and 2) that deletion of hematogenous macrophages will block the beneficial effects of peripheral TGF-¿-Smad 2/3 inhibition on Alzheimer pathology. PUBLIC HEALTH RELEVANCE: There are now over 3 million Americans afflicted with Alzheimer's disease, a figure that is projected to increase to 9 million by 2050, underscoring a rapidly developing public health problem. We propose that re-balancing TGF-¿ signaling in immune cells allows these cells to restrict the disease. If results from our Alzheimer's transgenic rat model establish the importance of this pathway, this could unveil a new therapeutic approach.

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆，其特征是A肽沉积为“老年性”淀粉样斑块、神经病理学和神经炎症。脑炎症最终未能减轻AD病理。然而，广泛抑制炎症并没有产生积极的信号，为AD的一级预防。这一证据和其他证据促使我们提出了一个总体假设：重新平衡炎症而不是完全关闭它可能对AD有益。主要的抑制性细胞因子转化生长因子-<$（TGF-<$）保持过度旺盛的炎症，以防止旁观者组织损伤。其他人已经证明，TGF-β 1 mRNA在AD患者脑中比健康老年人对照高约3倍，可能偏向于抑制性环境，其在限制脑淀粉样变性方面无效。我们在脑淀粉样变性小鼠模型中使用遗传和药理学方法的已发表和初步数据表明，（通过抑制）血原性单核吞噬细胞中TGF-β信号的再平衡促进其脑浸润和A β/A β-淀粉样蛋白清除。我们已经提出了一个工作假设，即重新平衡TGF-²信号传导可能会限制AD样病理。 充分检验这一假设的一个关键限制是无法获得忠实再现人类AD的动物模型。为了克服这一点，我们已经开发了一种新的大鼠模型的AD（线TgF 344-AD）的基础上共表达的突变型人淀粉样蛋白前体蛋白和早老素-1，每一个独立的原因早发性家族性AD。引人注目的是，TgF 344-AD大鼠表现出年龄依赖性脑淀粉样变性，其先于神经胶质增生、tau蛋白病、神经元损失和认知障碍。不像A- 驱动的转基因小鼠，其很好地模拟了脑淀粉样蛋白，但不是AD病理的全部谱，这些转基因大鼠发展为阿尔茨海默型的进行性神经变性。这种下一代AD大鼠模型将使基础和翻译AD研究成为可能，并提供了一个独特的机会来评估AD的“淀粉样蛋白级联假说”。 本提案的首要目标是利用TGF 344-AD大鼠来评价外周TGF-β信号传导的药理学抑制是否动员造血A β单核吞噬细胞以限制AD样病理。具体目标1的重点将是评估外周阻断TGF-β-Smad 2/3信号传导是否能预防或减缓导致神经病理学和认知能力下降的脑淀粉样变性。在具体目标2中，我们将确定外周TGF-β-Smad 2/3通路抑制是否治疗已建立的阿尔茨海默病并减少认知障碍。具体目标3将评估外周TGF-β信号传导阻断在转基因阿尔茨海默病大鼠中的有益作用是否是巨噬细胞依赖性的。我们在这一目标中的假设是双重的：1）外周TGF-β信号传导抑制将促进具有“交替M2”活化特征的造血A2吞噬细胞的脑浸润，以及2）造血巨噬细胞的缺失将阻断外周TGF-β-Smad 2/3抑制对阿尔茨海默病病理学的有益作用。 公共卫生相关性：现在有300多万美国人患有阿尔茨海默病，预计到2050年这一数字将增加到900万，这突出了一个迅速发展的公共卫生问题。我们认为，重新平衡免疫细胞中的TGF-β信号传导可以使这些细胞限制疾病。如果我们的阿尔茨海默氏症转基因大鼠模型的结果确立了这一途径的重要性，这可能会揭示一种新的治疗方法。