Role of BACE in the pathogenesis of Alzheimer's disease after head trauma

BACE 在头部外伤后阿尔茨海默病发病机制中的作用

• 批准号: 7728836
• 负责人: GIUSEPPINA TESCO
• 金额: $ 35.66万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728836
• 关键词: Ablation; Acute; Adaptor Signaling Protein; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Behavioral; Biochemical; Brain; Caspase; Cerebellum; Cerebral Ischemia; Chronic; Cleaved cell; Clinical; Cognitive deficits; Craniocerebral Trauma; Deposition; Development; Environmental Risk Factor; Enzymes; Event; Genes; Genetic; Goals; Human; In Vitro; Injury; Ischemia; Knockout Mice; Laboratories; Learning; Mediating; Memory impairment; Modeling; Molecular; Mus; Mutation; Outcome Study; Pathogenesis; Pathology; Patients; Pattern; Peptide Hydrolases; Peptides; Production; Protein Precursors; Proteins; Proteolysis; RNA Interference; Reporting; Risk; Risk Factors; Rodent; Role; Series; Site; Stress; Stroke; Synaptic Transmission; Technology; Temporal Lobe; Tg2576; Time; Transgenic Mice; Traumatic Brain Injury; Up-Regulation; Viral; Work; abeta deposition; base; beta secretase; controlled cortical impact; functional outcomes; gamma secretase; in vivo; knockout gene; mouse model; neurotoxic; novel; prevent; public health relevance; secretase; trafficking

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the strongest environmental risk factor for Alzheimer's disease (AD). Clinical and experimental TBI is associated with accelerated beta-amyloid (Abeta) deposition, a hallmark of AD pathology. The Abeta peptide is derived by serial proteolysis of amyloid precursor protein (APP) by beta-secretase at the N-terminus followed by gamma-secretase at the C-terminus. Beta-site APP-cleaving enzyme (BACE) has been identified as beta-secretase. BACE levels are elevated in AD brain, and BACE is induced as a stress-related protease following cerebral ischemia and TBI in rodents. We recently reported that BACE and beta-secretase activity increase following cerebral ischemia in vivo and caspase activation in vitro due to post-translational stabilization of BACE protein. We also found that the impaired degradation of BACE is due to caspase- mediated depletion of GGA3, an adaptor protein involved in BACE trafficking (Tesco et al. 2007). In the current proposal, we report that genetic ablation of GGA3 increases levels of BACE in the brain in vivo. Furthermore, we have found that GGA3 is depleted following TBI while BACE protein levels increase with a pattern similar to the one observed following cerebral ischemia. These new findings indicate that GGA3 depletion, mediated by caspase cleavage, and consequent BACE upregulation may be the common underlying mechanism of increased A? production following cerebral ischemia and TBI. Since Abeta has been shown to impair synaptic transmission, increased Abeta levels may be responsible for impaired functional outcome after TBI. This mechanism may also explain how TBI leads to increased risk of developing AD over time. In support of our hypothesis, we have found that GGA3 levels are decreased in both temporal cortex and cerebellum from AD subjects, suggesting that subjects with lower levels of GGA3 could be at greater risk of developing AD (Tesco et al. 2007). This may be particularly true for patients with stroke and TBI in which caspase activation occurs even in the chronic period after injury. The long-term goal of this proposal is to identify targets for novel treatments to prevent acute learning and memory deficits as well as development of AD following TBI. We propose the following specific aims: 1) determine the extent to which depletion of GGA3 regulates levels and activity of BACE and causes behavioral changes in mice; 2) determine the extent to which decreased levels of GGA3 affect BACE levels and activity and functional outcome following TBI in mice; 3) determine the extent to which lack or low levels of GGA3 exacerbate A? deposition in a mouse model of AD pathology (Tg2576 transgenic mice expressing human APP with the "Swedish" mutation (KM670/671NL)) in normal conditions and following TBI. PUBLIC HEALTH RELEVANCE: It has been known for several years that traumatic brain injury (TBI) can increase the risk of Alzheimer' s disease (AD), but the mechanism underlying that increased risk has not been understood. Our work shows that head trauma, can trigger a series of biochemical events that increase the production of beta-amyloid, the toxic peptide that accumulates in the brain of AD patients. Thus, we propose to use mouse models to determine whether the inhibition of ?-secretase, one of the enzymes responsible for the production of amyloid-beta, ameliorates the cognitive deficits and reduces AD pathology following head trauma. Furthermore, we propose to determine whether low levels of the trafficking molecule GGA3, which regulates b-secretase, may represent a novel risk factor for the development of cognitive deficits and AD following TBI using a mouse model in which the GGA3 gene has been deleted. Overall, the outcome of this study will help to identify novel therapies to prevent both short-term cognitive deficits and the development of AD in subjects affected by TBI.

描述（由申请人提供）：创伤性脑损伤（TBI）是阿尔茨海默病（AD）的最强环境危险因素。临床和实验性 TBI 与加速 β-淀粉样蛋白 (Abeta) 沉积有关，这是 AD 病理学的一个标志。 Abeta 肽是通过 N 端的 β 分泌酶和 C 端的 γ 分泌酶对淀粉样前体蛋白 (APP) 进行连续蛋白水解而衍生的。 β 位点 APP 裂解酶 (BACE) 已被鉴定为 β 分泌酶。 AD 脑中 BACE 水平升高，并且 BACE 在啮齿动物脑缺血和 TBI 后被诱导为应激相关蛋白酶。我们最近报道，由于 BACE 蛋白翻译后稳定，BACE 和 β-分泌酶活性在体内脑缺血和体外 caspase 激活后增加。我们还发现 BACE 降解受损是由于 caspase 介导的 GGA3 消耗所致，GGA3 是参与 BACE 运输的衔接蛋白 (Tesco et al. 2007)。在当前的提案中，我们报告了 GGA3 的基因消融增加了体内大脑中 BACE 的水平。此外，我们发现 TBI 后 GGA3 减少，而 BACE 蛋白水平增加，其模式与脑缺血后观察到的模式类似。这些新发现表明，由 caspase 裂解介导的 GGA3 耗竭以及随后的 BACE 上调可能是 A? 增加的共同潜在机制。脑缺血和 TBI 后产生。由于 Abeta 已被证明会损害突触传递，因此 Abeta 水平升高可能是 TBI 后功能受损的原因。这种机制也可以解释 TBI 如何随着时间的推移导致患 AD 的风险增加。为了支持我们的假设，我们发现 AD 受试者的颞叶皮层和小脑中的 GGA3 水平均下降，这表明 GGA3 水平较低的受试者患 AD 的风险可能更大（Tesco et al. 2007）。对于中风和 TBI 患者来说尤其如此，其中半胱天冬酶激活甚至在损伤后的慢性期也会发生。该提案的长期目标是确定新疗法的目标，以预防急性学习和记忆缺陷以及 TBI 后 AD 的发展。我们提出以下具体目标：1）确定 GGA3 的消耗在多大程度上调节 BACE 的水平和活性并导致小鼠行为改变； 2) 确定 GGA3 水平降低对小鼠 TBI 后 BACE 水平、活性和功能结果的影响程度； 3) 确定 GGA3 缺乏或低水平会在多大程度上加剧 A？在正常条件下和 TBI 后的 AD 病理小鼠模型（表达具有“瑞典”突变 (KM670/671NL) 的人类 APP 的 Tg2576 转基因小鼠）中沉积。公众健康相关性：多年来，人们都知道创伤性脑损伤 (TBI) 会增加患阿尔茨海默病 (AD) 的风险，但风险增加的潜在机制尚不清楚。我们的研究表明，头部外伤可以引发一系列生化事件，从而增加β-淀粉样蛋白的产生，β-淀粉样蛋白是一种在 AD 患者大脑中积聚的有毒肽。因此，我们建议使用小鼠模型来确定β-分泌酶（负责产生β淀粉样蛋白的酶之一）的抑制是否可以改善认知缺陷并减少头部外伤后的AD病理。此外，我们建议使用 GGA3 基因已被删除的小鼠模型来确定调节 b 分泌酶的运输分子 GGA3 的低水平是否可能代表 TBI 后认知缺陷和 AD 发展的新危险因素。总体而言，这项研究的结果将有助于确定新的疗法，以预防受 TBI 影响的受试者的短期认知缺陷和 AD 的发展。