Begum Aynun N, Yang Fusheng, Teng Edmond, Hu Shuxin, Jones Mychica R, Rosario Emily R, Beech Walter, Hudspeth Beverly, Ubeda Oliver J, Cole Greg M, Frautschy Sally A
Department of Medicine, University of California, Los Angeles, CA, USA.
J Alzheimers Dis. 2008 Dec;15(4):625-40. doi: 10.3233/jad-2008-15409.
The rat amyloid-beta (Abeta) intracerebroventricular infusion can model aspects of Alzheimer's disease (AD) and has predicted efficacy of therapies such as ibuprofen and curcumin in transgenic mouse models. High density lipoprotein (HDL), a normal plasma carrier of Abeta, is used to attenuate Abeta aggregation within the pump, causing Abeta-dependent toxicity and cognitive deficits within 3 months. Our goal was to identify factors that might accelerate onset of Abeta-dependent deficits to improve efficiency and cost-effectiveness of model. We focused on: 1) optimizing HDL-Abeta preparation for maximal toxicity; 2) evaluating the role of copper, a factor typically in water that can impact oligomer stability; and 3) determining impact of insulin resistance (type II diabetes), a risk factor for AD. In vitro studies were performed to determine doses of copper and methods of Abeta-HDL preparation that maximized toxicity. These preparations when infused resulted in earlier onset of cognitive deficits within 6 weeks post-infusion. Induction of insulin resistance did not exacerbate Abeta-dependent cognitive deficits, but did exacerbate synaptic protein loss. In summary, the newly described in vivo infusion model may be useful cost-effective method for screening for new therapeutic drugs for AD.
大鼠脑室内注射淀粉样β蛋白（Aβ）可模拟阿尔茨海默病（AD）的某些方面，并已在转基因小鼠模型中预测了布洛芬和姜黄素等疗法的疗效。高密度脂蛋白（HDL）是Aβ的正常血浆载体，用于减轻泵内Aβ的聚集，在3个月内导致Aβ依赖性毒性和认知缺陷。我们的目标是确定可能加速Aβ依赖性缺陷发作的因素，以提高模型的效率和成本效益。我们关注以下几点：1）优化HDL-Aβ制剂以实现最大毒性；2）评估铜的作用，铜是一种通常存在于水中的因素，可影响寡聚体稳定性；3）确定胰岛素抵抗（II型糖尿病）的影响，胰岛素抵抗是AD的一个风险因素。进行了体外研究，以确定使毒性最大化的铜剂量和Aβ-HDL制剂方法。这些制剂注入后，在注入后6周内导致认知缺陷更早出现。胰岛素抵抗的诱导并未加剧Aβ依赖性认知缺陷，但确实加剧了突触蛋白的损失。总之，新描述的体内注射模型可能是一种用于筛选AD新治疗药物的有用且具有成本效益的方法。
