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

约翰霍普金斯大学阿尔茨海默病研究中心（ADRC）的项目2名为“AD的抗淀粉样蛋白疗法建模：认知恢复的潜力”。本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。该项目将测试低聚a - β物种的积累会损害学习和记忆的假设，这些认知障碍可以通过抑制a - β的产生来逆转。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）。强力霉素可以抑制这些小鼠a - β的产生。初步数据表明，在强力霉素抑制a - β后，淀粉样蛋白沉积稳定，但记忆缺陷逐渐改善。这一发现

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.