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: 8335480
• 负责人: Yong Shen
• 金额: $ 37.37万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8335480
• 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）在临床上以起病隐袭的痴呆为特征；病理学上，其特征是存在大量神经炎斑、神经原纤维缠结和进行性神经变性。有极其有力的证据表明，A¿ 的异常组装具有神经毒性，并且在 AD 中发挥关键作用。为什么 A¿ 增加并积累或诱发神经变性尚不清楚。 然而，AD大脑中斑块形成和神经退行性变的机制尚不清楚。我们最近描述（He et al., 2007），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（Shen 等人，1997）证明，与 TNFRI（TNF 死亡受体）不同，TNFRII 可以保护神经元。为了检查 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 APP23 小鼠与 TNFRII 敲除小鼠杂交，在 APP23 小鼠 (APP23/TNFRII-/-) 中产生 TNFRII 敲除 (TNFRII-/-)。我们的初步结果表明，APP23/TNFRII-/- 小鼠在 12 月龄时具有更多的 A¿ 斑块和增加的 A¿ 水平。因此，我们提出一个中心假设：调节 TNF II 型受体活性可以通过 NF-:B 依赖性和独立的细胞内信号通路改变 BACE1、A¿ 的产生和 AD 神经病理学。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 AD 样病理。如果是这样，我们将研究其机制，例如TNFRII可能通过NF-kB依赖性和非NF-kB依赖性方式通过新的信号转导途径介导BACE1，以及这些机制最终如何产生神经保护作用。我们相信，实验的成功完成将带来新的治疗干预措施。 本申请的目的是确定 TNFRII 在神经元和小鼠大脑中的调节方式、它如何影响 A¿ 及其前体的生成，以及 TNFRII 生成的增加是否可以保护和改善小鼠的神经退行性病变和 AD 样疾病。我们期望鉴定 TNFRII 表达的调节剂以及与 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。如果成功的话，我们的发现可能会为 AD 和神经退行性疾病的治疗提供新的靶点。 公共健康相关性：神经元和突触损失是阿尔茨海默病 (AD) 大脑最显着的特征。目前 AD 治疗还不够充分，因此许多新的治疗理念值得学术界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一个潜在的靶点，例如用于 AD 治疗的 TNF II 型受体 (TNFRII)。我们最近开始了一项很有前景的临床试验，使用抑制 TNF 信号通路的药物对 AD 患者进行治疗，该试验已获得 FDA 批准和 NIH 授予。因此，阐明 BACE1 的调节机制可以识别新的潜在治疗靶点，从而减少直接靶向 BACE1 可能产生的副作用。