Amyloid-beta precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-beta (Abeta) peptide found in neuritic plaques of Alzheimer's disease (AD) patients. Because Abeta shows neurotoxic properties, and because familial forms of AD promote Abeta accumulation, a massive international research effort has been aimed at understanding the mechanisms of Abeta generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPalpha (sAPPalpha), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Abeta appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Abeta, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Abeta, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease.

中文翻译：

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淀粉样蛋白前体蛋白及其片段在调节神经活动，可塑性和记忆中的作用。

淀粉样β前体蛋白（APP）是跨膜蛋白，具有大的细胞外结构域和小得多的细胞内结构域。它是在阿尔茨海默氏病（AD）患者神经炎斑块中发现的淀粉样β（Abeta）肽的来源。由于Abeta具有神经毒性特性，并且由于AD的家族形式促进Abe​​ta积累，因此国际上的大量研究工作都旨在了解Abeta的产生，分解代谢和毒性的机制。然而，APP是一种极其复杂的分子，在其全长构型中可能是功能上重要的分子，并且是对神经功能有不同影响的众多片段的来源。例如，源自非淀粉样蛋白加工途径的一个片段，即分泌的APPalpha（sAPPalpha）具有神经保护作用，具有神经营养作用并调节细胞兴奋性和突触可塑性，而Abeta似乎发挥相反的作用。人们对其他片段的神经功能知之甚少，但是人们越来越了解APP的基本生物学，因为人们已经认识到，疾病状态期间APP片段功能活性的改变将对细胞功能产生复杂的影响。实际上，已经提出，某些蛋白质片段的水平或活性的降低，除了Aβ的积累外，可能在与AD有关的认知功能障碍中，特别是在疾病早期，起着关键作用。要测试和修改该假设，重要的是要了解全长APP及其片段通常在神经元结构和功能中所起的作用。在这里，我们将审查解决这些基本问题的证据，特别注意APP片段在突触传递和神经可塑性中的作用，因为这些可能是了解它们对学习和记忆的影响的关键。从这些文献中可以清楚地看出，APP片段（包括Abeta）可以对关键的神经功能，包括急性和长期的细胞兴奋性，突触传递和长期增强产生强大的调节作用。此外，有少量但正在增长的文献证实这些片段相应地调节了行为学习和记忆。这些数据表明，AD中认知功能障碍的完整说明将需要纳入APP片段完整补充的作用。为此，