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

阿尔茨海默病(AD)是一种复杂的疾病，受多个基因的作用及其相互作用的影响 彼此之间以及与环境之间的关系。创伤性脑损伤(TBI)是环境影响最大的疾病之一。 AD的危险因素。脑外伤被认为可以加速AD的发病和损伤的严重程度 与增加的风险呈正相关。越来越多的令人信服的证据表明，单一的TBI事件与 在人类和动物模型中，随着Aβ和淀粉样蛋白沉积水平的增加。我们和其他人都有 结果表明，实验性脑创伤后BACE1水平显著升高，提示BACE1 海拔升高可能是头部创伤后A-β产生增加的原因。然而，分子 这种损伤后BACE1升高的机制在很大程度上仍不清楚。我们之前已经 研究表明，BACE1在啮齿动物脑缺血后增加，并提出caspase介导的 BACE1相互作用分子GGA3(高尔基体定位的含γ-EAR的ARF结合蛋白3)缺失 BACE1升高的潜在机制。我们已经确定GGA3是caspase-3底物，并且 这种GGA3的缺失通过损害BACE1对溶酶体的分选来稳定BACE1，而溶酶体通常是被降解的。我们 另有报道称，死后GGA3水平降低，并与BACE1水平呈负相关 广告头脑。最近，我们报道了GGA3及其同系物GGA1被耗尽，而BACE1水平 脑外伤小鼠模型和死后阿尔茨海默病脑损伤后急性期增加。我们进一步 通过显示BACE1水平增加，证明了GGA3在体内调节BACE1的作用 在GGA3缺失小鼠的大脑中。此外，对GGA3缺失小鼠的广泛行为分析表明， GGA3的基因缺失会产生一种行为表型，这表明GGA3在大脑中扮演着特定的角色。 我们还确定，在体外，异位表达GGA3会降低BACE1和Aβ的水平。因此， 我们建议：1)确定GGA3缺失小鼠的行为表型依赖于 BACE1在大脑特定区域的升高；2)确定BACE1过度表达的程度 GGA3在体内以半胱氨酸酶依赖的方式降低BACE1和Aβ的水平；3)确定 在脑损伤的小鼠模型中，缺失GGA_1和GGA_3会增加BACE1和A_β的水平。

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.