MODELING AND ANTI-AMYLOID THERAPY FOR AD: POTENTIAL FOR COGNITIVE RECOVERY

约翰霍普金斯阿尔茨海默病研究中心（ADRC）的项目2名为“AD的抗淀粉样蛋白治疗建模：认知恢复的潜力”。该项目的重点是寡聚淀粉样蛋白-β（A-β）肽在与阿尔茨海默病（AD）相关的认知障碍中的作用。该项目将测试以下假设：寡聚A-β物质的积累损害学习和记忆，这些认知障碍可以通过抑制A-β产生来逆转。为了解决这个问题，我们将使用A-β淀粉样变性的小鼠模型，其中突变淀粉样前体蛋白（APP）的表达由四环素调节的启动子控制（这些转基因小鼠被称为TetOffAPP小鼠）。在这些小鼠中，A-β的产生可以用多西环素抑制。初步数据表明，在用多西环素抑制A-β后，淀粉样蛋白沉积是稳定的，但是，记忆缺陷逐渐改善。这一发现 （1）目的1：确定在遗传诱导的APP表达和新的A-β产生停滞后，来源于新合成的A-β肽的寡聚体A-β种类的减少是否改善条件TetOffAPP小鼠模型中的学习和记忆。(2)目标二：为了确定突触损伤的恢复是否与A-β产生后的认知改善相关，将在记忆缺陷显著改善的小鼠中评估神经元活性的突触、突触能和立即早期基因标志物。(3)目标3：研究CNS单胺系统中神经退行性变化与TetOffAPP小鼠A-β肽减少后观察到的认知恢复程度的关系。总的来说，这些研究的结果将通过评估寡聚体A-β引起突触损伤后功能修复和恢复的程度来解决关于AD抗淀粉样蛋白治疗策略的价值的重要问题。对靶向A-β产生的治疗干预的结果进行评价将为临床试验中的适当预期提供信息。

Project 2 of the Johns Hopkins Alzheimer's Disease Research Center (ADRC) is titled "Modeling an anti-amyloid therapy for AD: potential for cognitive recovery". This project focuses the role of oligomeric amyloid-beta (A-beta) peptides in the cognitive impairment associated with Alzheimer's disease (AD). The project will test the hypothesis that accumulation of oligomeric A-beta species impairs learning and memory and that these cognitive impairments can be reversed with suppression of A-beta generation. To address this question we will use a mouse model of A-beta amyloidosis in which the expression of mutant amyloid precursor protein (APP) is controlled by a tetracycline-regulated promoter (these transgenic mice are known as TetOffAPP mice). A-beta production can be suppressed in these mice with doxycycline. Preliminary data suggest that following A-beta suppression with doxycycline, amyloid deposits are stable but there is, nevertheless, a gradual amelioration of the memory deficits. This finding has led to the following three specific aims: (1) Aim 1: To determine whether the reduction of oligomoeric A-beta species derived from newly-synthesized A-beta peptides improves learning and memory in the conditional TetOffAPP mouse models after genetically induced arrest of APP expression and new A-beta production. (2) Aim 2: To determine whether recovery of synaptic damage is associated with cognitive improvement after A-beta production - synaptic, glutamatergic and immediate early gene markers of neuronal activity will be assessed in mice with significant amelioration of memory deficits. (3) Aim 3: To examine the role of neurodegenerative changes in CNS monoamine systems in relation to the degree of cognitive recovery observed after reduction of A-beta peptides in the TetOffAPP mice. Collectively, outcomes from these studies will address an important issue regarding the value of an anti-amyloid therapeutic strategy for AD by assessing the magnitude of functional repair and recovery after synaptic damage by oligomeric A-beta. Evaluation of outcomes of therapeutic interventions that target A-beta production will inform appropriate expectations in clinical trials.