Therapeutic potential of GMF suppresssion in inflammation and neurodegeneration

 描述(申请人提供)：阿尔茨海默病(AD)是老年人中最常见的痴呆症形式，影响着500万美国人和全球2500多万人。AD是一种与年龄相关的神经退行性疾病，在工业化国家，65岁以上的人约有7%，80岁以上的人约有40%。AD的特征是淀粉样斑块(AP)和神经原纤维缠结(NFT)的积聚，导致最终的神经元死亡。研究表明，NFT这一定义特征与AD患者痴呆的临床表现有很好的相关性。星形胶质细胞和小胶质细胞在炎症反应中的作用可能有助于该病的发病。这种炎症反应涉及细胞因子的产生，这些细胞因子与氧化应激和应激激活的信号转导事件有着复杂的联系。阿尔茨海默病的症状以记忆力丧失、进行性认知障碍以及各种行为和神经精神障碍为特征。阿尔茨海默病的病因尚不清楚，但其危险因素包括遗传、生物和环境因素。然而，目前还没有明确的治疗AD的方法。目前的建议建立在我们之前的工作的基础上，这些工作为我们的假设提供了支持，即胶质细胞成熟因子(GMF)参与了与神经退行性疾病，特别是AD相关的神经元退行性变。我们建议研究细胞内GMF与AD的病理生理学相关的假设，以及研究抑制内源性GMF功能作为一种有效和选择性的策略来减缓甚至逆转致病过程的有效性。我们将追求两个具体目标。在目标1中，我们将验证一种假设，即进展性AD的发病机制与GMF表达增强有关，并且GMF优先定位于AD患者脑区的淀粉样斑块和神经原纤维缠结部位。我们将检查临床诊断和神经病理证实的AD患者和年龄和性别匹配的非痴呆对照组的脑组织。我们将定量评估AP、NFTs、反应性胶质细胞(神经保护和神经毒性表型)的区域密度，并确定与AD和年龄匹配的非痴呆对照组中GMF的患病率、分布和浓度的关系。在目的2中，我们将评估(A)GMF特异性shRNA和(B)GMF特异性抗体在两种AD相关病理生理学动物模型中抑制GMF功能的效果：(1)5XFAD小鼠表达5种不同的突变(APP中3种，早老素-1中2种)；(2)rTg4510小鼠互变模型。我们将在炎症和神经退变的背景下评估GMF功能抑制策略；比较组织病理学特征、神经化学变化和认知记忆功能。这项研究具有重要的临床意义，并提供了一种有效的体内方法来测试转基因食品抑制剂作为神经退行性疾病的治疗剂。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia among elderly, affecting 5 million Americans and over 25 million individuals worldwide. AD is an age-related neurodegenerative disease, with approximately 7% of people older than 65 years and about 40% of people older than 80 years being affected in industrialized countries. AD is characterized by the accumulation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) leading to eventual neuronal death. Studies have shown that NFTs, a defining feature correlated well with the clinical expression of dementia in AD. The role of astrocytes and microglia in mounting an inflammatory response could contribute to the pathogenesis of the disease. Such inflammatory response involves the production of cytokines that are intricately linked to the oxidative stress and stress-activated signal transduction events. The symptoms of AD are characterized by loss of memory, progressive impairment of cognition, and various behavioral and neuropsychiatric disturbances. The etiology of AD remains unknown, but the risk factors include genetic, biological and environmental factors. However, there is no definite treatment yet available for AD. Current proposal builds on our previous work that has provided support for our hypothesis that glia maturation factor (GMF) is involved in neuronal degeneration associated with neurodegenerative diseases, especially AD. We propose to investigate the hypothesis that intracellular GMF is associated with the pathophysiology of AD, as well as investigating the effectiveness of suppression of endogenous GMF-function as an effective and selective strategy to slow, and perhaps reverse, pathogenic processes. Two Specific Aims will be pursued. In Aim 1, we will test the hypothesis that the progressive AD pathogenesis is associated with the enhanced GMF expression and GMF is preferentially localized to sites of amyloid plaques and neurofibrillary tangles in AD affected brain regions. We will examine brain tissues from clinically diagnosed and neuropathologically confirmed AD cases and age- and gender-matched non-demented controls. We will quantitatively evaluate the regional densities of APs, NFTs, reactive glia (neuroprotective and neurotoxic phenotypes), and determine relationship to the prevalence, distribution and concentration of GMF in AD and age-matched non-demented controls. In Aim 2, we will evaluate the effects of suppression of GMF-functions with (A) GMF-specific shRNA, and (B) GMF-specific antibody in two animal models of AD-relevant pathophysiology: (1) 5XFAD mouse expressing 5 different mutations (3 in APP and 2 in presenilin-1), and (2) rTg4510 mouse model of tauopathy. We will evaluate the GMF-function suppression strategy in the context of inflammation and neurodegeneration; compare the histopathological features, neurochemical changes, and cognitive memory functions. The present study has significant clinical implications, and provides an efficient in vivo approach to test GMF-inhibitors as therapeutic agents for neurodegenerative diseases.