Alzheimer’s disease (AD) is a leading cause of age-related dementia worldwide. Despite more than a century of intensive research, we are not anywhere near the discovery of a cure for this disease or a way to prevent its progression. Among the various molecular mechanisms proposed for the description of the pathogenesis and progression of AD, the amyloid cascade hypothesis, according to which accumulation of a product of amyloid precursor protein (APP) cleavage, amyloid β (Aβ) peptide, induces pathological changes in the brain observed in AD, occupies a unique niche. Although multiple proteins have been implicated in this amyloid cascade signaling pathway, their structure–function relationships are mostly unexplored. However, it is known that two major proteins related to AD pathology, Aβ peptide, and microtubule-associated protein tau belong to the category of intrinsically disordered proteins (IDPs), which are the functionally important proteins characterized by a lack of fixed, ordered three-dimensional structure. IDPs and intrinsically disordered protein regions (IDPRs) play numerous vital roles in various cellular processes, such as signaling, cell cycle regulation, macromolecular recognition, and promiscuous binding. However, the deregulation and misfolding of IDPs may lead to disturbed signaling, interactions, and disease pathogenesis. Often, molecular recognition-related IDPs/IDPRs undergo disorder-to-order transition upon binding to their biological partners and contain specific disorder-based binding motifs, known as molecular recognition features (MoRFs). Knowing the intrinsic disorder status and disorder-based functionality of proteins associated with amyloid cascade signaling pathway may help to untangle the mechanisms of AD pathogenesis and help identify therapeutic targets. In this paper, we have used multiple computational tools to evaluate the presence of intrinsic disorder and MoRFs in 27 proteins potentially relevant to the amyloid cascade signaling pathway. Among these, BIN1, APP, APOE, PICALM, PSEN1 and CD33 were found to be highly disordered. Furthermore, their disorder-based binding regions and associated short linear motifs have also been identified. These findings represent important foundation for the future research, and experimental characterization of disordered regions in these proteins is required to better understand their roles in AD pathogenesis.

阿尔茨海默氏病（AD）是世界范围内与年龄有关的痴呆症的主要原因。尽管进行了长达一个多世纪的深入研究，但我们距离发现该病的治疗方法或预防其发展的途径还很遥远。在用于描述AD发病机理和进展的各种分子机制中，淀粉样蛋白级联假设是淀粉样蛋白前体蛋白（APP）裂解产物淀粉样β（Aβ）肽的积累，可引起AD的病理变化。在AD中观察到的大脑占有独特的位置。尽管淀粉样蛋白级联信号通路中涉及多种蛋白质，但它们的结构-功能关系尚待探索。但是，已知与AD病理相关的两种主要蛋白是Aβ肽，与微管相关的蛋白tau属于内在无序蛋白（IDP）的类别，它们是功能上重要的蛋白，其特征在于缺乏固定的，有序的三维结构。IDP和内在无序的蛋白质区域（IDPR）在各种细胞过程中起着至关重要的作用，例如信号传导，细胞周期调控，大分子识别和混杂结合。但是，IDP的失调和错误折叠可能会导致信号传导，相互作用和疾病发病机制受到干扰。通常，与分子识别相关的IDP / IDPR在与其生物伴侣结合后会经历从无序到有序的转变，并包含特定的基于无序的结合基序，称为分子识别特征（MoRF）。了解与淀粉样蛋白级联信号通路相关的蛋白质的内在疾病状态和基于疾病的功能，可能有助于弄清AD发病机理，并帮助确定治疗靶标。在本文中，我们使用了多种计算工具来评估与淀粉样蛋白级联信号通路潜在相关的27种蛋白中内在障碍和MoRF的存在。其中，发现BIN1，APP，APOE，PICALM，PSEN1和CD33高度无序。此外，还鉴定了它们基于疾病的结合区和相关的短线性基序。这些发现为将来的研究奠定了重要基础，并且需要对这些蛋白质中的无序区域进行实验表征，以更好地了解其在AD发病机理中的作用。