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

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症，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。脑部炎症最终无法减轻阿尔茨海默病的病理。然而，广泛抑制炎症并没有对阿尔茨海默病一级预防产生积极的信号。这和其他证据提示了我们的首要假设：重新平衡炎症而不是完全关闭炎症可能对阿尔茨海默病有益。主要的抑制性细胞因子转化生长因子- - (TGF- -)可以抑制过度活跃的炎症，防止旁观者组织损伤。其他研究表明，TGF- 1 mRNA在阿尔茨海默病患者大脑中比健康老年人对照组高出约3倍，这可能倾向于抑制环境，对限制脑淀粉样变性无效。我们在小鼠脑淀粉样变性模型中使用遗传和药理学方法的已发表和初步数据表明，通过抑制造血单核吞噬细胞中TGF-信号的重新平衡促进了它们的脑浸润和A - / -淀粉样蛋白的清除。我们已经提出了一个工作假设，即重新平衡TGF- β信号可能会限制ad样病理。充分验证这一假设的一个关键限制是无法获得忠实再现人类阿尔茨海默病的动物模型。为了克服这一点，我们基于突变的人类淀粉样蛋白前体蛋白和早老素-1的共同表达，开发了一种新的AD大鼠模型（TgF344-AD系），这两种蛋白都是早发性家族性AD的独立原因。引人注目的是，TgF344-AD大鼠表现出年龄依赖性的大脑淀粉样变性，其发生在胶质瘤、牛头病、神经元丧失和认知障碍之前。与A驱动的转基因小鼠不同，转基因小鼠可以很好地模拟大脑淀粉样蛋白，但不能模拟AD的全部病理，这些转基因大鼠会发展为阿尔茨海默氏型的进行性神经退行性变。这种下一代AD大鼠模型将使AD的基础和转译研究成为可能，并为评估AD的“淀粉样蛋白级联假说”提供了独特的机会。本研究的总体目标是利用TgF344-AD大鼠来评估外周TGF-信号的药理抑制是否能动员血A -单核吞噬细胞来限制AD样病理。特异性目的1的重点将是评估外周阻断TGF- α - smad 2/3信号是否能预防或减缓导致神经病理和认知能力下降的脑淀粉样变性。在Specific Aim 2中，我们将确定外周TGF- α - smad 2/3通路抑制是否能治疗既定的阿尔茨海默病并减轻认知障碍。特异性目的3将评估外周TGF- β信号阻断在转基因老年痴呆症大鼠中的有益作用是否依赖于巨噬细胞。我们的假设有两个方面：1)外周TGF- 2信号抑制将促进具有“替代M2”激活谱的血源性A2吞噬细胞的脑浸润；2)血源性巨噬细胞的缺失将阻断外周TGF- 2 - smad 2/3抑制对阿尔茨海默病的有益作用。

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.