Department of Psychology, University of Otago, PO Box 56, Dunedin, New Zealand; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
Department of Anatomy, School of Biomedical Sciences, University of Otago, PO Box 56, Dunedin, New Zealand; Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
Semin Cell Dev Biol. 2023 Apr;139:93-101. doi: 10.1016/j.semcdb.2022.05.014. Epub 2022 May 30.
Soluble amyloid precursor protein-alpha (sAPPα) is a multi-functional brain-derived protein that has neuroprotective, neurogenic and neurotropic properties. Moreover, it is known to facilitate synaptic function and promote neural repair. These properties suggest sAPPα may be useful as a therapeutic agent for the treatment of neurological diseases characterized by synaptic failure and neuronal loss, such as occurs in Alzheimer's disease, and for neural repair following traumatic brain injury and stroke. However, sAPPα's relatively large size and the difficulty of ongoing delivery of therapeutics to the brain mean this is not currently practicable. Importantly, however, sAPPα is composed of several neuroactive domains that each possess properties that collectively are remarkably similar to those of sAPPα itself. Here, we review the molecular structure of sAPPα and identify the domains that contribute to its overall functionality. Four peptide motifs present as possible targets for therapeutic development. We review their physiochemical and neuroactive properties, both within sAPPα and as isolated peptides, and discuss their potential for future development as multipurpose therapeutic agents for the treatment of Alzheimer's disease and other disorders of neuronal function. Further, we discuss the role of heparin binding sites, found within sAPPα's structure and overlapping with the neuroactive domains, as sites for interactions with effector proteins and synaptic receptors. The potential role of the neuroactive peptides known as Cationic Arginine-Rich Peptides (CARPs) as neuroprotective motifs is also reviewed. Mechanisms of peptide delivery to the brain are briefly discussed. Finally, we summarise the potential benefits and pitfalls of using the isolated peptides, either individually or in combination, for the treatment of neurological diseases.
可溶性淀粉样前体蛋白-α（sAPPα）是一种多功能的脑源性蛋白，具有神经保护、神经生成和神经营养特性。此外，它已知能够促进突触功能并促进神经修复。这些特性表明，sAPPα 可能作为治疗剂用于治疗以突触功能衰竭和神经元丧失为特征的神经疾病，例如阿尔茨海默病，以及用于创伤性脑损伤和中风后的神经修复。然而，sAPPα 的相对较大尺寸以及向大脑持续输送治疗剂的困难意味着这在目前是不可行的。然而，重要的是，sAPPα 由几个具有神经活性的结构域组成，每个结构域都具有共同特性，这些特性与 sAPPα 本身非常相似。在这里，我们综述了 sAPPα 的分子结构，并确定了对其整体功能有贡献的结构域。有四个肽基序可能作为治疗开发的靶点。我们综述了它们在 sAPPα 内和作为分离肽时的物理化学和神经活性特性，并讨论了它们作为治疗阿尔茨海默病和其他神经元功能障碍的多用途治疗剂的未来发展潜力。此外，我们还讨论了肝素结合位点在 sAPPα 结构内的作用及其与神经活性结构域重叠的作用，作为与效应蛋白和突触受体相互作用的位点。我们还综述了称为阳离子精氨酸丰富肽（CARPs）的神经活性肽作为神经保护基序的潜在作用。简要讨论了肽向大脑的递药机制。最后，我们总结了使用分离肽单独或联合使用治疗神经疾病的潜在益处和陷阱。
