Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives

Although great advances in elucidating the molecular basis and pathogenesis of Alzheimer's disease (AD) have been made and multifarious novel therapeutic approaches have been developed, AD remains an incurable disease. Evidence shows that AD neuropathology occurs decades before clinical presentation. AD is divided into three stages: preclinical stage, mild cognitive impairment (MCI), and AD dementia. In the natural world, some animals, such as non-human primates (NHPs) and canines, can develop spontaneous AD-like dementia. However, most animals do not develop AD. With the development of transgenic techniques, both invertebrate and vertebrate animals have been employed to uncover the mechanisms of AD and study treatment methods. Most AD research focuses on early-onset familial AD (FAD) because FAD is associated with specific genetic mutations. However, there are no well-established late-onset sporadic AD (SAD) animal models because SAD is not directly linked to any genetic mutation, and multiple environmental factors are involved. Moreover, the widely used animal models are not able to sufficiently recapitulate the pathological events that occur in the MCI or preclinical stages. This review summarizes the common models used to study AD, from yeast to NHP models, and discusses the different applications, evaluation methods, and challenges related to AD animal models, as well as prospects for the evolution of future studies.近年来，虽然人们对阿尔茨海默病（Alzheimer’s disease，AD）的分子学基础和发病机制的研究均取得了较大进展，各种新的治疗方法层出不穷，但就目前而言，阿尔茨海默病仍是一种不治之症。有证据表明，AD神经病理学改变在出现临床表现的几十年之前就有可能发生。AD大致可以分为三个阶段：临床前阶段、轻度认知障碍（Mild cognitive impairment，MCI）阶段和AD痴呆阶段。自然界中有一些动物，如非人类的灵长类动物和犬科动物，可以自发的形成AD样痴呆，但大多数动物不会发展出AD样表现。随着转基因技术的发展，无脊椎动物和脊椎动物都被广泛用于揭示AD的发病机制和研究治疗方法。大多数AD研究集中在早发型AD（即家族型AD），因为家族性AD与特定的基因突变相关。与之相对应的晚发型AD（即散发型AD），由于其与基因突变没有直接联系，且涉及多种环境因素，目前还没有完善的散发型AD动物模型。此外，目前广泛使用的动物模型还不能充分再现MCI或临床前阶段发生的一系列病理改变。该文从酵母模型到非人灵长类动物模型系统综述了目前用于研究AD的常用模型，在此基础上讨论了AD动物模型的不同应用、评价方法、面临的挑战以及未来研究的发展前景。.