Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
CNS Neurosci Ther. 2012 Jan;18(1):47-56. doi: 10.1111/j.1755-5949.2010.00221.x. Epub 2010 Dec 27.
The memory dysfunctions that characterize Alzheimer's disease (AD) are strongly correlated with synapse loss. The amyloid precursor protein (APP) and its cleavage product Aβ play central roles in synapse and memory loss, and thus are strongly implicated in the pathogenesis of AD. Numerous in vitro and transgenic AD mouse model studies have shown that overexpression of APP leads to Aβ accumulation, which causes decreased synaptic activity and dendritic spine density. However, the normal synaptic function of APP itself is not fully understood. Several recent studies have found that full-length APP promotes synaptic activity, synapse formation, and dendritic spine formation. These findings cast APP as a potential key player in learning and memory. It is of interest that the synaptic functions of full-length APP are opposite to the effects associated with pathological Aβ accumulation. In this review, we will summarize the normal functions of APP at synapses and spines along with other known functions of APP, including its role in cell motility, neuronal migration, and neurite outgrowth. These studies shed light on the physiological actions of APP, independent of Aβ effects, and thus lead to a better understanding of the synaptic dysfunctions associated with AD.
阿尔茨海默病（AD）的记忆功能障碍与突触丧失密切相关。淀粉样前体蛋白（APP）及其裂解产物 Aβ 在突触和记忆丧失中起核心作用，因此强烈提示其与 AD 的发病机制有关。大量的体外和转基因 AD 小鼠模型研究表明，APP 的过表达导致 Aβ 积累，从而导致突触活性和树突棘密度降低。然而，APP 本身的正常突触功能尚不完全清楚。最近的几项研究发现全长 APP 促进突触活性、突触形成和树突棘形成。这些发现表明 APP 是学习和记忆的潜在关键参与者。有趣的是，全长 APP 的突触功能与与病理性 Aβ 积累相关的作用相反。在这篇综述中，我们将总结 APP 在突触和树突棘上的正常功能以及 APP 的其他已知功能，包括其在细胞迁移、神经元迁移和神经突生长中的作用。这些研究阐明了 APP 的生理作用，与 Aβ 效应无关，从而更好地理解与 AD 相关的突触功能障碍。
