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: 8534659
• 负责人: Yong Shen
• 金额: $ 35.31万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8534659
• 关键词: Adverse effects; Affect; Age-Months; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Area; Award; Behavioral; Brain; Breeding; Cell Line; Cessation of life; Cleaved cell; Clinical Trials; Cognition; Communities; Dementia; Disease; Event; Exhibits; FDA approved; Generations; Genetic; Goals; Health; Human; In Vitro; Knock-out; Knockout Mice; Lead; Learning; Mediating; Memory impairment; Messenger RNA; Mus; NF-kappa B; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Fragments; Pharmaceutical Preparations; Pharmacologic Substance; Production; Proteins; Regulation; Reporting; Research; Resistance; Role; Senile Plaques; Signal Pathway; Signal Transduction Pathway; Subfamily lentivirinae; Synapses; TNF gene; TRAF2 gene; Testing; Tg2576; Toxic effect; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; United States National Institutes of Health; amyloid precursor protein processing; beta-site APP cleaving enzyme 1; improved; in vitro activity; in vivo; mouse model; mutant; neuron loss; neuropathology; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutic intervention; overexpression; progressive neurodegeneration; protein expression; receptor; research study; secretase; therapeutic target

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(申请人提供)：阿尔茨海默病(AD)临床上以潜伏性痴呆为特征，病理上以大量神经炎性斑块、神经原纤维缠结和进行性神经变性为特征。有非常有力的证据表明，异常的A？组装是神经毒性的，在AD中起着关键作用。为什么Aé增加，并积累或诱导神经变性，目前尚不清楚。然而，阿尔茨海默病脑内斑块形成和神经变性的机制尚不清楚。我们最近(他等人，2007)描述了斑块的主要成分淀粉样蛋白2(A？)的产生受到TNFRI缺失的抑制，TNFRI缺失通过NF-：B途径降低BACE1水平。然而，我们在体外证明了(沈等人，1997年)，与作为肿瘤坏死因子死亡受体的TNFRI不同，TNFRII保护神经元。为了研究TNFRII在APP加工中的作用，我们将表达突变型APP并形成许多A斑块的AD转基因APP23小鼠与TNFRII基因敲除小鼠杂交，在APP23小鼠中产生TNFRII基因敲除(TNFRII-/-)(APP23/TNFRII-/-)。我们的初步结果表明，APP23/TNFRII-/-小鼠在12个月龄时有更多的A？斑块和升高的A？水平。因此，我们提出了一个中心假设，即调节肿瘤坏死因子II型受体活性可以通过依赖和独立的细胞内信号通路改变BACE1、A？的产生和AD的神经病理。我们将使用双转基因小鼠模型APP23/TNFRII-/-来检查这些小鼠是否表现出早期的AD样病理。如果是这样的话，我们将研究其机制，如可能的TNFRII通过新的信号转导途径通过依赖和非依赖的方式介导BACE1，以及这些机制是如何最终导致神经保护的。我们相信，实验的成功完成将带来新的治疗干预措施。这项应用的目标是确定TNFRII在神经元和小鼠大脑中是如何调节的，它如何影响A？及其前体的产生，以及增加TNFRII的产生是否可能保护和改善小鼠的神经退行性变和AD样疾病。我们希望确定TNFRII表达的调节因子和与TNFRII相互作用的蛋白质。我们还期望确定TNFRII是AD发病机制的主要修饰物，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AD和神经退行性变的治疗提供新的靶点。 与公共卫生相关：神经元和突触丢失是阿尔茨海默病(AD)大脑最显著的特征。目前AD的治疗方法还不够完善，因此许多新的治疗方法值得学术界和药学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通路是AD治疗的一个潜在靶点，与肿瘤坏死因子II型受体(TNFRII)类似。我们最近开始了一项有希望的临床试验，在AD患者身上使用一种抑制肿瘤坏死因子信号通路的药物，该药物获得了FDA的批准和NIH的奖励。因此，阐明BACE1的调控机制可以确定新的潜在治疗靶点，从而减少直接靶向BACE1可能产生的副作用。