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@ARTICLE{Liu:278922,
      author       = {Liu, Haiyan and Bui, Quoc and Hassenstab, Jason and Gordon,
                      Brian A and Benzinger, Tammie L S and Timsina, Jigyasha and
                      Sung, Yun Ju and Karch, Celeste and Renton, Alan E and
                      Daniels, Alisha and Morris, John C and Xiong, Chengjie and
                      Ibanez, Laura and Perrin, Richard J and Llibre-Guerra, Jorge
                      J and Day, Gregory S and Supnet-Bell, Charlene and Xu, Xiong
                      and Berman, Sarah B and Chhatwal, Jasmeer P and Ikeuchi,
                      Takeshi and Kasuga, Kensaku and Niimi, Yoshiki and Huey,
                      Edward D and Schofield, Peter R and Brooks, William S and
                      Ryan, Natalie S and Jucker, Mathias and Laske, Christoph and
                      Levin, Johannes and Vöglein, Jonathan and Roh, Jee Hoon and
                      Lopera, Francisco and Bateman, Randall J and Cruchaga,
                      Carlos and McDade, Eric M},
      collaboration = {team, For DIAN study},
      title        = {{U}biquitin-proteasome system in the different stages of
                      dominantly inherited {A}lzheimer's disease.},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {5},
      issn         = {1552-5260},
      address      = {Hoboken, NJ},
      publisher    = {Wiley},
      reportid     = {DZNE-2025-00648},
      pages        = {e70243},
      year         = {2025},
      abstract     = {This study investigated the role of the
                      ubiquitin-proteasome system (UPS) in dominantly inherited
                      Alzheimer's disease (DIAD) by examining cerebrospinal fluid
                      (CSF) levels of UPS proteins.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.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.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.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.},
      keywords     = {Humans / Alzheimer Disease: genetics / Alzheimer Disease:
                      cerebrospinal fluid / Alzheimer Disease: pathology /
                      Ubiquitin: cerebrospinal fluid / Proteasome Endopeptidase
                      Complex: cerebrospinal fluid / Proteasome Endopeptidase
                      Complex: metabolism / Female / Male / Biomarkers:
                      cerebrospinal fluid / tau Proteins: cerebrospinal fluid /
                      Disease Progression / Middle Aged / Aged / Mutation:
                      genetics / Amyloid beta-Peptides: cerebrospinal fluid /
                      Adult / amyloid beta (Other) / amyloid precursor protein
                      (Other) / autophagy–lysosome pathway (Other) / biomarker
                      discovery (Other) / dominantly inherited Alzheimer's disease
                      (Other) / genetic mutations (Other) / neurodegeneration
                      (Other) / presenilin 1 (Other) / presenilin 2 (Other) /
                      protein aggregation (Other) / protein degradation (Other) /
                      proteomic analysis (Other) / proteostasis (Other) / tau
                      pathology (Other) / ubiquitin–proteasome system (Other) /
                      Ubiquitin (NLM Chemicals) / Proteasome Endopeptidase Complex
                      (NLM Chemicals) / Biomarkers (NLM Chemicals) / tau Proteins
                      (NLM Chemicals) / Amyloid beta-Peptides (NLM Chemicals)},
      cin          = {AG Jucker / AG Gasser / AG Levin / Clinical Research
                      (Munich)},
      ddc          = {610},
      cid          = {I:(DE-2719)1210001 / I:(DE-2719)1210000 /
                      I:(DE-2719)1111016 / I:(DE-2719)1111015},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40411302},
      pmc          = {pmc:PMC12102666},
      doi          = {10.1002/alz.70243},
      url          = {https://pub.dzne.de/record/278922},
}