Section for Clinical Chemistry, Department of Translational Medicine, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary.
Front Immunol. 2021 Oct 12;12:750665. doi: 10.3389/fimmu.2021.750665. eCollection 2021.
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia worldwide. In AD, neurodegeneration spreads throughout different areas of the central nervous system (CNS) in a gradual and predictable pattern, causing progressive memory decline and cognitive impairment. Deposition of neurofibrillary tangles (NFTs) in specific CNS regions correlates with the severity of AD and constitutes the basis for disease classification into different Braak stages (I-VI). Early clinical symptoms are typically associated with stages III-IV (i.e., limbic stages) when the involvement of the hippocampus begins. Histopathological changes in AD have been linked to brain proteome alterations, including aberrant posttranslational modifications (PTMs) such as the hyperphosphorylation of Tau. Most proteomic studies to date have focused on AD progression across different stages of the disease, by targeting one specific brain area at a time. However, in AD vulnerable regions, stage-specific proteomic alterations, including changes in PTM status occur in parallel and remain poorly characterized. Here, we conducted proteomic, phosphoproteomic, and acetylomic analyses of human postmortem tissue samples from AD (Braak stage III-IV, n=11) and control brains (n=12), covering all anatomical areas affected during the limbic stage of the disease (total hippocampus, CA1, entorhinal and perirhinal cortices). Overall, ~6000 proteins, ~9000 unique phosphopeptides and 221 acetylated peptides were accurately quantified across all tissues. Our results reveal significant proteome changes in AD brains compared to controls. Among others, we have observed the dysregulation of pathways related to the adaptive and innate immune responses, including several altered antimicrobial peptides (AMPs). Notably, some of these changes were restricted to specific anatomical areas, while others altered according to disease progression across the regions studied. Our data highlights the molecular heterogeneity of AD and the relevance of neuroinflammation as a major player in AD pathology. Data are available ProteomeXchange with identifier PXD027173.
阿尔茨海默病（AD）是一种神经退行性疾病，也是全球最常见的痴呆症病因。在 AD 中，神经退行性病变以渐进且可预测的模式在中枢神经系统（CNS）的不同区域扩散，导致进行性记忆衰退和认知障碍。特定 CNS 区域神经原纤维缠结（NFT）的沉积与 AD 的严重程度相关，并构成疾病分类为不同 Braak 阶段（I-VI）的基础。早期临床症状通常与 III-IV 期（即边缘系统期）相关，此时海马体开始受累。AD 的组织病理学变化与大脑蛋白质组改变有关，包括 Tau 的异常翻译后修饰（PTMs），如过度磷酸化。迄今为止，大多数蛋白质组学研究都集中在疾病的不同阶段的 AD 进展上，每次针对一个特定的大脑区域。然而，在 AD 易损区域，包括 PTM 状态变化在内的阶段特异性蛋白质组改变同时发生，并且特征描述较差。在这里，我们对 AD（Braak 阶段 III-IV，n=11）和对照脑（n=12）的人类死后组织样本进行了蛋白质组学、磷酸蛋白质组学和乙酰化蛋白质组学分析，涵盖了疾病边缘期受累的所有解剖区域（总海马体、CA1、内嗅皮层和旁嗅皮层）。总体而言，在所有组织中准确定量了约 6000 种蛋白质、约 9000 种独特的磷酸肽和 221 种乙酰化肽。与对照组相比，我们在 AD 大脑中发现了显著的蛋白质组变化。其中，我们观察到与适应性和先天免疫反应相关的途径失调，包括几种改变的抗菌肽（AMPs）。值得注意的是，这些变化中的一些仅限于特定的解剖区域，而另一些则根据研究区域的疾病进展而改变。我们的数据突出了 AD 的分子异质性以及神经炎症作为 AD 病理学主要参与者的重要性。数据可在 ProteomeXchange 中以标识符 PXD027173 获得。
