In Vivo Application of beta Amyloid Oligomers: A Simple Tool to Evaluate Mechanisms of Action and New Therapeutic Approaches
In Vivo Application of beta Amyloid Oligomers: A Simple Tool to Evaluate Mechanisms of Action and New Therapeutic Approaches
复制标题
DOI：
10.2174/13816128113199990497
复制
发表时间：
2014-05-01
影响因子：
3.1
通讯作者：
Forloni, Gianluigi
中科院分区：
文献类型：
--
作者：
Balducci, Claudia;Forloni, Gianluigi
阿尔茨海默病（AD）是一种神经退行性疾病，其特征在于细胞外淀粉样蛋白β（A β）的脑积聚和由过度磷酸化的tau蛋白制成的神经元缠结，这两种主要病变在疾病进展期间相继出现。在过去的十年中，许多研究已经提出A β的小的可溶性聚集体，称为寡聚体，作为负责AD的典型的突触功能障碍、记忆丧失和神经变性的种类。体外和体内实验已经鉴定出A β寡聚体作为可以通过可逆机制改变突触功能的元素，当暴露持续时，这种机制逐渐变得永久。在这里，我们表明，在小鼠脑室内（ICV）注射含有特定A β（1-42）寡聚体的溶液时，在新的物体识别任务的测试，大大影响他们的记忆。这种急性小鼠模型使我们能够区分寡聚体是否影响记忆处理的特定阶段。在记忆巩固之前单次注射A β（1-42）寡聚体会破坏信息加工，导致记忆障碍，而一旦信息加工完成后注射，则没有观察到这种影响，表明寡聚体影响记忆巩固而不是提取。除了A β（1-42），A β（1-40）寡聚体也损害记忆，这两种亚型都被抗A β 4G 8单克隆抗体所拮抗，这一简单可靠的范例有助于研究A β寡聚体干扰神经元过程的机制，并测试针对这些物种的新治疗方法的疗效。我们通过与A β寡聚体直接共孵育、在A β寡聚体之前进行ICV注射以及用穿过血脑屏障的药物进行全身治疗来测试几种分子。我们还研究了细胞朊蛋白作为寡聚体诱导的记忆障碍的介质的参与。
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cerebral accumulation of extracellular amyloid beta (A beta) and neurofibrillary tangles made of hyperphosphorylated tau protein, two main lesions which appear sequentially during the disease progression. In the last decade numerous studies have proposed small soluble aggregates of A beta, known as oligomers, as the species responsible for synaptic dysfunction, memory loss and neurodegeneration typical of AD. In vitro and in vivo experiments have identified A beta oligomers as the elements that can alter synaptic function by a reversible mechanism, which gradually becomes permanent when exposure is continuous. Here we show that intracerebroventricular (ICV) injection in mice of a solution containing specifically A beta(1-42) oligomers substantially affects their memory when tested in the novel object recognition task. This acute mouse model enabled us to distinguish whether oligomers were affecting specific phases of the memory processing. A single injection of A beta(1-42) oligomers before memory consolidation abolished information processing, leading to memory impairment, whereas no such effects were observed when the injection was done once the information had been processed, indicating that the oligomers affect memory consolidation rather than retrieval. Beside A beta(1-42), A beta(1-40) oligomers also impaired memory, and both isoforms were antagonized by the anti-A beta 4G8 monoclonal antibody.This simple and reliable paradigm is useful to investigate the mechanisms through which A beta oligomers interfere with neuronal processes and to test the efficacy of new therapeutic approaches specifically against these species. We tested several molecules by direct co-incubation with A beta oligomers, ICV injections preceding A beta oligomers, and the systemic treatment with drugs that cross the blood brain barrier. We also examined the proposed involvement of cellular prion protein as a mediator of the oligomer-induced memory impairment.