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

基本信息

批准号：
8932290
负责人：
GIUSEPPINA TESCO
金额：
$ 41.25万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8932290
关键词：
Acute Affect Alanine Alzheimer&apos s Disease Amygdaloid structure Amyloid beta-Protein Amyloid deposition Animal Model Animals Anti-Anxiety Agents Aspartate Behavioral Binding Proteins Biochemical Brain Brain region Caspase Cerebral Ischemia Complex Craniocerebral Trauma Development Disease Ear Ectopic Expression Environment Environmental Risk Factor Enzymes Event Fright Generations Genes Genetic Goals Golgi Apparatus Head Homologous Gene Human In Vitro Injury Knockout Mice Lysosomes Mediating Molecular Mus Outcome Study Pathogenesis Pathology Patients Peptides Phase Phenotype Prevention Production Regulation Reporting Resistance Risk Rodent Role Series Severity of illness Site Small Interfering RNA Sorting - Cell Movement Transgenic Mice Transgenic Organisms Traumatic Brain Injury Wild Type Mouse Work beta-site APP cleaving enzyme 1 caspase-3 in vivo mouse model new therapeutic target overexpression prevent trafficking

项目摘要

Alzheimer’s disease (AD) is a complex disease influenced by the actions of multiple genes, their interactions with each other and with the environment. Traumatic brain injury (TBI) is one of the most robust environmental risk factors for AD. TBI has been suggested to accelerate the onset of AD and the severity of the injury positively correlates with increased risk. Compelling evidence is mounting that a single TBI event is associated with increased levels of Aβ and amyloid deposition both in humans and animal models. We, and others, have demonstrated that BACE1 levels are dramatically increased following experimental TBI suggesting that BACE1 elevation may be responsible for increased Aβ production following head trauma. However the molecular mechanisms responsible for this post-injury elevation of BACE1 remain largely unknown. We have previously shown that BACE1 increases following cerebral ischemia in rodents and proposed that caspase-mediated depletion of the BACE1 interacting molecule GGA3 (Golgi-localized γ-ear-containing ARF binding protein 3) is the underlying mechanism of BACE1 elevation. We have determined that GGA3 is a caspase-3 substrate and that GGA3 depletion stabilizes BACE1 by impairing its sorting to lysosomes where it is normally degraded. We also reported that levels of GGA3 are decreased and inversely correlated with BACE1 levels in post-mortem AD brains. More recently, we reported that GGA3 and its homologue GGA1 are depleted while BACE1 levels increase in the acute phase post-injury in a mouse model of TBI and in post-mortem AD brains. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. Moreover, extensive behavioral analysis of GGA3 null mice has revealed that genetic deletion of GGA3 produces a behavioral phenotype suggesting a specific role for GGA3 in the brain. We have also determined that ectopic expression of GGA3 decreases levels of BACE1 and Aβ in vitro. Thus, we propose: 1) to determine the extent to which the behavioral phenotype of GGA3 null mice depends on BACE1 elevation in specific region of the brains; 2) to determine the extent to which the over-expression of GGA3 reduces levels of BACE1 and Aβ in a caspase-dependent fashion in vivo; 3) to determine the extent to which depletion of GGA1 and GGA3 increases levels of BACE1 and Aβ in a mouse model of TBI.

阿尔茨海默氏病（AD）是一种复杂的疾病，受多个基因的作用影响，它们的相互作用彼此和环境。创伤性脑损伤（TBI）是最健壮的环境之一 AD的风险因素。已建议TBI加速AD的发作和受伤的严重程度与风险的增加相关。令人信服的证据表明，单个TBI事件与在人类和动物模型中，Aβ和淀粉样蛋白沉积水平的水平升高。我们和其他人有证明在实验TBI之后，BACE1水平急剧增加，表明BACE1 抬高可能导致头部创伤后Aβ产生增加。但是分子负责这种BACE1的伤害后升高的机制仍然很大未知。我们以前有表明BACE1在啮齿动物中的脑缺血后增加，并提出caspase介导的 BACE1相互作用GGA3的耗竭（高尔基体定位的γ-ear-Arf ARF结合蛋白3） BACE1高程的基本机制。我们已经确定GGA3是caspase-3底物，并且 GGA3部署通过损害其对溶酶体通常降解的溶酶体的分类来稳定BACE1。我们还报道了GGA3的水平降低并与验尸中的BACE1水平成反比广告大脑。最近，我们报道GGA3及其同源GGA1耗尽，而BACE1水平在TBI小鼠模型和验尸后的大脑中，急性期伤害后增加。我们进一步通过证明BACE1水平的增加，证明了GGA3在体内的BACE1调节中的作用在GGA3无效小鼠的大脑中。此外，GGA3无效小鼠的广泛行为分析表明 GGA3的遗传缺失会产生一种行为表型，这表明GGA3在大脑中具有特定的作用。我们还确定，GGA3的生态表达在体外降低了BACE1和Aβ的水平。那，我们建议：1）确定GGA3无效小鼠的行为表型的程度大脑特定区域的BACE1升高； 2）确定过表达的程度 GGA3在体内以caspase依赖性方式降低BACE1和Aβ的水平； 3）确定范围在TBI小鼠模型中，GGA1和GGA3的耗竭增加了BACE1和Aβ的水平。