Ubiquitin-proteasome system in the different stages of dominantly inherited Alzheimer's disease.
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Liu Haiyan, Bui Quoc, Hassenstab Jason, Gordon Brian A, Benzinger Tammie L S, Timsina Jigyasha, Sung Yun Ju, Karch Celeste, Renton Alan E, Daniels Alisha, Morris John C, Xiong Chengjie, Ibanez Laura, Perrin Richard J, Llibre-Guerra Jorge J, Day Gregory S, Supnet-Bell Charlene, Xu Xiong, Berman Sarah B, Chhatwal Jasmeer P, Ikeuchi Takeshi, Kasuga Kensaku, Niimi Yoshiki, Huey Edward D, Schofield Peter R, Brooks William S, Ryan Natalie S, Jucker Mathias, Laske Christoph, Levin Johannes, Vöglein Jonathan, Roh Jee Hoon, Lopera Francisco, Bateman Randall J, Cruchaga Carlos, McDade Eric M, For DIAN study team
Аннотация
METHOD: The SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.
RESULTS: Subtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS-activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late-stage tau biomarkers, microglia, and axonal degeneration.
DISCUSSION: The rise in UPS proteins alongside tau-related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.
HIGHLIGHTS: This study investigates the ubiquitin-proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late-stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau-pathology-driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.