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: 8505324
• 负责人: GIUSEPPINA TESCO
• 金额: $ 30.61万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8505324
• 关键词: Ablation; Acute; Adaptor Signaling Protein; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; 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; 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; 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.

描述（由申请人提供）：创伤性脑损伤（TBI）是阿尔茨海默氏病（AD）的最强环境风险因素。临床和实验性TBI与AD病理学标志的加速β-淀粉样蛋白（ABETA）沉积有关。 ABETA肽是通过β-分泌酶在N末端对淀粉样蛋白前体蛋白（APP）的序列蛋白水解得出的，然后在C-末端是γ-分泌酶。 Beta位置APP交流酶（BACE）已被确定为β-分泌酶。 AD大脑中的贝斯水平升高，盲目脑缺血和啮齿动物中TBI后，阳离子作为应力相关蛋白酶诱导。我们最近报道说，由于BACE蛋白的翻译后稳定化，体内脑缺血和胱天蛋白酶激活后的巴斯和β-分泌酶活性在体外和胱天蛋白酶激活后增加。我们还发现，BACE的降解受损是由于caspase介导的GGA3的耗竭，GGA3是一种参与BACE运输的衔接蛋白（Tesco等，2007）。在当前的提案中，我们报告说，GGA3的遗传消融会增加体内大脑的束缚水平。此外，我们发现GGA3在TBI之后耗尽，而BACE蛋白水平随着与脑缺血后观察到的模式相似的模式增加。这些新发现表明，由胱天蛋白酶裂解介导的GGA3耗竭以及随之而来的贝斯上调可能是增加A的常见基本机制？脑缺血和TBI之后的产生。由于已显示ABETA会损害突触传播，因此ABETA水平的提高可能导致TBI后功能结果受损。这种机制还可以解释TBI如何导致随着时间的推移发展AD的风险增加。为了支持我们的假设，我们发现AD受试者的颞皮质和小脑的GGA3水平都降低，这表明GGA3水平较低的受试者可能会更大的风险发展AD（Tesco等，2007）。对于中风和TBI的患者，即使在受伤后的慢性时期，胱天蛋白酶激活也可能尤其如此。该提案的长期目标是确定新型治疗方法的目标，以防止急性学习和记忆缺陷以及TBI后AD的发展。我们提出以下特定目的：1）确定GGA3的耗竭在多大程度上调节贝丝的水平和活动，并导致小鼠行为变化； 2）确定小鼠TBI后GGA3水平降低的程度如何影响BACE水平，活动和功能结果； 3）确定缺乏或低水平的GGA3加重A的程度？在正常条件下和TBI之后，在具有“瑞典”突变（KM670/671NL）表达人类应用的AD病理小鼠模型（TG2576转基因小鼠）中沉积。