McDade Eric, Liu Haiyan, Bui Quoc, Hassenstab Jason, Gordon Brian, Benzinger Tammie, Shen Yuanyuan, Timsina Jigyasha, Wang Lihua, Sung Yun Ju, Karch Celeste, Renton Alan, Daniels Alisha, Morris John, Xiong Chengjie, Ibanez Laura, Perrin Richard, Llibre-Guerra Jorge J, Day Gregory, Supnet-Bell Charlene, Xu Xiong, Berman Sarah, Chhatwal Jasmeer, Ikeuchi Takeshi, Kasuga Kensaku, Niimi Yoshiki, Huey Edward, Schofield Peter, Brooks William, Ryan Natalie, Jucker Mathias, Laske Christoph, Levin Johannes, Vöglein Jonathan, Roh Jee Hoon, Lopera Francisco, Bateman Randall, Cruchaga Carlos
Washington University in St. Louis.
Washington University Medical School.
Res Sq. 2024 Jul 23:rs.3.rs-4202125. doi: 10.21203/rs.3.rs-4202125/v1.
This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating (CDR). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR. Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis.
本研究通过检测泛素-蛋白酶体系统（UPS）蛋白的脑脊液（CSF）水平变化，以及疾病进展、AD成像生物标志物（PiB PET、tau PET）、神经退行性变成像指标（MRI、FDG PET）和临床痴呆评定量表（CDR），探讨了泛素-蛋白酶体系统在显性遗传性阿尔茨海默病（DIAD）中的作用。使用SOMAscan检测法，我们在估计症状出现前长达二十年的时间里，检测到突变携带者（MCs）中与蛋白质稳态相关的特定泛素酶有细微增加。随后，UPS激活酶，包括E2和E3蛋白以及泛素相关修饰因子出现更明显的升高。我们的研究结果还表明，UPS蛋白与CSF生物标志物之间存在一致的相关性，如Aβ42/40比值、总tau、各种磷酸化tau物种与总tau的比值（ptau181/T181、ptauT205/T205、ptauS202/S202、ptauT217/T217）以及MTBR-tau243，同时与神经丝轻链（NfL）和CDR也相关。值得注意的是，观察到与成像标志物（PiB PET、tau PET）呈正相关，与神经退行性变标志物（FDG PET、MRI）呈负相关，突出了UPS失调与神经退行性变过程之间的重要联系。这些相关性表明，多种UPS蛋白随着tau水平和tau缠结相关标志物的升高而增加，表明UPS在错误折叠的tau/神经原纤维缠结（NFTs）和症状发作方面可能发挥作用。这些发现表明，DIAD MCs中CSF中UPS蛋白升高可作为疾病进展的早期指标，并提示UPS失调与淀粉样斑块、tau缠结形成之间存在联系，这意味着UPS可能是AD发病机制中的一个潜在治疗靶点。
