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: 8900365
• 负责人: TERRENCE C TOWN
• 金额: $ 36.09万
• 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: 2011-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900365
• 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; Early Onset Familial Alzheimer' s Disease; 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; 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; amyloid peptide; base; brain cell; cytokine; inhibitor/antagonist; killings; macrophage; mouse model; mutant; neuroinflammation; neuron loss; neuropathology; next generation; novel; novel therapeutic intervention; peptide A; 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.

描述(申请人提供)：阿尔茨海默病(AD)是最常见的痴呆症，其特点是A�多肽沉积，如‘老年性’�-淀粉样斑块、神经病理学和神经炎症。脑部炎症最终无法缓解AD的病理。然而，广泛抑制炎症并没有为AD的一级预防产生积极的信号。这一证据和其他证据促使我们提出了最重要的假设：重新平衡炎症而不是完全切断炎症可能对AD有利。主要的抑制性细胞因子转化生长因子-�(转化生长因子-�)抑制过度活跃的炎症，以防止旁观者组织损伤。其他研究表明，AD患者大脑中的转化生长因子-�1m RNA是健康老年对照组的~3倍，这可能倾向于一种抑制环境，而这种环境在限制脑淀粉样变性方面无效。我们用遗传学和药理学方法在小鼠脑淀粉样变性模型上发表的初步数据表明，通过抑制血源性单核巨噬细胞中转化生长因子-�信号的重新平衡促进了它们的脑渗透和A-�/�-淀粉样蛋白清除。我们提出了一个工作假说，即重新平衡转化生长因子-�信号可能会限制AD样病理。完全验证这一假说的一个关键限制是无法获得真实再现人类阿尔茨海默病的动物模型。为了克服这一点，我们开发了一种新的AD大鼠模型(TgF344-AD)，该模型基于突变的人类淀粉样前体蛋白和早老素-1的共表达，两者都是早发性家族性AD的独立原因。值得注意的是，TgF344-AD大鼠表现出年龄依赖性的脑淀粉样变性，先于胶质增生、节段性病变、神经元丢失和认知障碍。与�驱动的转基因小鼠不同，后者很好地模拟了大脑淀粉样蛋白，但不是AD病理的全部谱系，这些转基因大鼠发展为阿尔茨海默型进行性神经退行性变。这一新一代AD大鼠模型将使AD的基础和转化性研究成为可能，并为评估AD的“淀粉样级联假说”提供了一个独特的机会。该方案的主要目的是利用TgF344-AD大鼠评估药物抑制外周血转化生长因子-�信号是否动员血源性A-�单核巨噬细胞来限制AD样病理。具体目标1的重点将是评估外周阻断转化生长因子-�-SMAD2/3信号通路是否阻止或减缓导致神经病理和认知功能下降的脑淀粉样变性。在特定的目标2中，我们将确定外周抑制转化生长因子-�-SMAD2/3通路是否治疗阿尔茨海默病和减少认知障碍。具体目标3将评估外周转化生长因子-�信号阻断对转基因阿尔茨海默病大鼠的益处是否依赖于巨噬细胞。我们的假设有两个：1)外周抑制转化生长因子-�信号将促进血源性A2吞噬细胞在脑内的渗透，其激活模式为“交替M2”；2)外周血源性巨噬细胞的缺失将阻断外周转化生长因子-�-Smad2/3抑制对阿尔茨海默病病理的有利作用。