BACE1 regulation and TNFR Type II receptor in Alzheimers disease

阿尔茨海默病中的 BACE1 调节和 TNFR II 型受体

• 批准号: 8049800
• 负责人: Yong Shen
• 金额: $ 38.88万
• 依托单位: ROSKAMP INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049800
• 关键词: BACE1; regulation; TNFR; Type; II

DESCRIPTION (provided by applicant): Clinically, Alzheimer's disease (AD) is characterized by dementia of insidious onset; pathologically, it is characterized by the presence of numerous neuritic plaques, neurofibrillary tangles, and a progressive Neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of A¿ are neurotoxic and have a key role in AD. Why A¿ is increased and accumulates or induces Neurodegeneration is unclear. However, the mechanisms of plaque formation and neurodegeneration in AD brains are not clear. We recently described (He et al., 2007) that generation of amyloid 2 (A¿), the main component of plaques, is inhibited by TNFRI deletion, which reduces BACE1 levels via the NF-:B pathway. However, we demonstrated in vitro (Shen et al., 1997) that, unlike TNFRI, which is the TNF death receptor, TNFRII, protects neurons. To examine the roles of TNFRII in APP processing, we cross-bred AD transgenic APP23 mice, which express mutant APP and form many A¿ plaques, with TNFRII knockout mice, to generate TNFRII knockout (TNFRII-/-) in APP23 mice (APP23/TNFRII-/-). Our preliminary results demonstrated that APP23/TNFRII-/- mice have more A¿ plaques and increased A¿ levels at 12 months of age. Thus, we propose a central hypothesis that modulation of TNF type II receptor activity can alter BACE1, A¿ production and AD neuropathology via NF-:B-dependent and independent intracellular signaling pathways. We will use the double transgenic mouse model, APP23/TNFRII-/-, to examine whether these mice exhibit earlier AD-like pathology. If so, we will study the mechanisms, such as possible TNFRII mediated BACE1 through new signal transduction pathways by NF-kB dependent and non-NF-kB dependent manner, and how these mechanisms ultimately result in neuroprotection. We believe that successful completion of the experiments will lead to novel therapeutic interventions. The goal of this application is to determine how TNFRII is regulated in neurons and in mouse brains, how it affects the generation of A¿ and its precursors, and whether increased production of TNFRII may be protective and ameliorate Neurodegeneration and AD-like disease in mice. We expect to identify modulators of TNFRII expression and proteins that interact with TNFRII. We also expect to establish that TNFRII is a major modifier of AD pathogenesis and that increasing TNFRII levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration. PUBLIC HEALTH RELEVANCE: Neuronal and synaptic losses are the most prominent features in the Alzheimer's disease (AD) brain. AD treatments are presently inadequate, so numerous novel therapy ideas deserve rigorous exploration in the academic and pharmaceutical research communities. Inhibition of tumor necrosis factor and its mediated signal transduction pathway is one potential target area, like TNF type II receptor (TNFRII) for AD treatment. We recently have started a promising clinical trial with a drug inhibiting TNF signal pathway on AD patients, which is FDA approved and NIH awarded. Thus, elucidating the regulatory mechanisms for BACE1 could identify new potential therapeutic targets and therefore diminish possible side effects that could arise by directly targeting BACE1.

描述（由申请人提供）：临床上，阿尔茨海默病（AD）的特征在于隐匿性发作的痴呆;病理学上，其特征在于存在大量神经炎性斑块、神经纤维缠结和进行性神经变性。有非常强有力的证据表明，A？的异常组装是神经毒性的，在AD中起着关键作用。为什么A？增加和积累或诱导神经变性尚不清楚。 然而，AD脑内斑块形成和神经退行性变的机制尚不清楚。我们最近描述了（He et al.，2007），淀粉样蛋白2（A）（斑块的主要成分）的产生被TNFRI缺失抑制，TNFRI缺失通过NF-：B途径降低BACE 1水平。然而，我们在体外证明了（Shen等人，1997），与TNFRI不同，TNFRII是TNF死亡受体，保护神经元。为了研究TNFRII在APP加工中的作用，我们将表达突变APP并形成许多A？斑块的AD转基因APP 23小鼠与TNFRII敲除小鼠杂交，以在APP 23小鼠（APP 23/TNFRII-/-）中产生TNFRII敲除（TNFRII-/-）。我们的初步结果表明，APP 23/TNFRII-/-小鼠在12月龄时有更多的A？斑块和增加的A？水平。因此，我们提出了一个中心假设，即TNF II型受体活性的调节可以通过NF-：B依赖性和独立的细胞内信号传导途径改变BACE 1，A？产生和AD神经病理学。我们将使用双转基因小鼠模型，APP 23/TNFRII-/-，以检查这些小鼠是否表现出早期AD样病理。如果是这样的话，我们将研究其机制，如TNFRII介导的BACE 1可能通过新的信号转导途径，通过NF-κ B依赖和非NF-κ B依赖的方式，以及这些机制如何最终导致神经保护。我们相信，实验的成功完成将导致新的治疗干预。 本申请的目的是确定TNFRII如何在神经元和小鼠大脑中调节，它如何影响A？及其前体的产生，以及TNFRII的产生增加是否可以保护和改善小鼠的神经变性和AD样疾病。我们期望确定TNFRII表达的调节剂和与TNFRII相互作用的蛋白质。我们还期望确定TNFRII是AD发病机制的主要调节剂，并且增加TNFRII水平可以减少疾病。如果成功，我们的发现可能为治疗AD和神经退行性疾病提供新的靶点。 公共卫生相关性：神经元和突触损失是阿尔茨海默病（AD）大脑中最突出的特征。AD治疗目前是不够的，所以许多新的治疗思路值得在学术和药物研究界进行严格的探索。抑制肿瘤坏死因子及其介导的信号转导途径是治疗AD的一个潜在靶点，如TNF II型受体（TNFRII）。我们最近已经开始了一项有希望的临床试验，用一种药物抑制AD患者的TNF信号通路，这是FDA批准和NIH授予。因此，阐明BACE 1的调节机制可以确定新的潜在治疗靶点，从而减少直接靶向BACE 1可能产生的副作用。