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

 描述（由申请人提供）：阿尔茨海默病（AD）是一种复杂的疾病，受多个基因的作用、它们彼此之间的相互作用以及与环境的相互作用的影响。创伤性脑损伤（TBI）是AD最强大的环境危险因素之一。TBI已被认为加速AD的发作，并且损伤的严重程度与风险增加呈正相关。越来越多的令人信服的证据表明，在人类和动物模型中，单一TBI事件与Aβ和淀粉样蛋白沉积水平增加相关。我们和其他人已经证明，实验性TBI后BACE 1水平升高，表明BACE 1升高可能是头部创伤后Aβ产生增加的原因。然而，负责这种损伤后BACE 1升高的分子机制在很大程度上仍然未知。我们先前已经证明啮齿类动物脑缺血后BACE 1增加，并提出半胱天冬酶介导的BACE 1相互作用分子GGA 3（高尔基体定位的含γ-ear的ARF结合蛋白3）的耗竭是BACE 1升高的潜在机制。我们已经确定GGA 3是半胱天冬酶-3底物，并且GGA 3消耗通过损害其分选到溶酶体（在溶酶体中其通常被降解）来稳定BACE 1。我们还报道了死后AD脑中GGA 3水平降低，并与BACE 1水平呈负相关。最近，我们报道了在TBI小鼠模型和死后AD脑中，GGA 3及其同源物GGA 1在急性期损伤后耗尽，而BACE 1水平增加。我们通过显示BACE 1水平在GGA 3缺失小鼠的脑中增加，进一步证明了GGA 3在体内BACE 1调节中的作用。此外，对GGA 3缺失小鼠的广泛行为分析已经揭示，GGA 3的遗传缺失产生行为表型，表明GGA 3在脑中的特定作用。我们还确定了GGA 3的异位表达降低了体外BACE 1和Aβ的水平。因此，我们建议：1）确定GGA 3缺失小鼠的行为表型依赖于脑的特定区域中的BACE 1升高的程度; 2）确定GGA 3缺失小鼠的行为表型依赖于脑的特定区域中的BACE 1升高的程度; GGA 3的消耗在体内以半胱天冬酶依赖性方式降低BACE 1和Aβ的水平; 3）确定GGA 1和GGA 3的消耗在TBI小鼠模型中增加BACE 1和Aβ水平的程度。

 DESCRIPTION (provided by applicant): 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 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.