Ubiquitin–proteasome system in the different stages of dominantly inherited Alzheimer's disease
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.
Authors
- Tammie L.S. Benzinger (ORCID: https://orcid.org/0000-0002-8114-0552)
- Jee Hoon Roh (ORCID: https://orcid.org/0000-0002-3243-0529)
- Alan E. Renton (ORCID: https://orcid.org/0000-0001-6702-8268)
- Celeste M M. Karch (ORCID: https://orcid.org/0000-0002-6854-5547)
- Mathias Jucker (ORCID: https://orcid.org/0000-0001-9045-1072)
- Richard J. Perrin (ORCID: https://orcid.org/0000-0002-3443-7716)
- Peter R. Schofield (ORCID: https://orcid.org/0000-0003-2967-9662)
- Randall John Bateman (ORCID: https://orcid.org/0000-0002-7729-1702)
- Sarah Berman (ORCID: https://orcid.org/0000-0002-5096-4962)
- Takeshi Ikeuchi (ORCID: https://orcid.org/0000-0001-8828-8085)
- Xu Xiong (ORCID: https://orcid.org/0000-0001-9292-5059)
- Yoshiki Niimi (ORCID: https://orcid.org/0000-0002-2556-8167)
- Jonathan Vöglein (ORCID: https://orcid.org/0000-0002-5965-838X)
- Johannes Levin (ORCID: https://orcid.org/0000-0001-5092-4306)
- Yan V. Sun (ORCID: https://orcid.org/0000-0002-2838-1824)
- Carlos C Cruchaga (ORCID: https://orcid.org/0000-0002-0276-2899)
- Charlene Supnet (ORCID: https://orcid.org/0000-0001-6917-770X)
- Kensaku Kasuga (ORCID: https://orcid.org/0000-0002-2178-0769)
- William S. Brooks (ORCID: https://orcid.org/0000-0001-8603-4233)
- Alisha Daniels (ORCID: https://orcid.org/0009-0001-1464-6465)
- Francisco Lopera (ORCID: https://orcid.org/0000-0002-5238-0231)
- Chengjie Xiong (ORCID: https://orcid.org/0000-0003-0044-4499)
- Quoc Bui (ORCID: https://orcid.org/0000-0001-6692-5602)
- Jason Hassenstab (ORCID: https://orcid.org/0000-0002-7802-3371)
- Gregory Scott Day (ORCID: https://orcid.org/0000-0001-5133-5538)
- Eric McDade (ORCID: https://orcid.org/0000-0002-6764-3866)
- Laura Ibáñez (ORCID: https://orcid.org/0000-0003-2381-7059)
- Edward D. Huey (ORCID: https://orcid.org/0000-0002-8295-5884)
- Natalie S. Ryan (ORCID: https://orcid.org/0000-0003-0361-7455)
- Jasmeer P. Chhatwal (ORCID: https://orcid.org/0000-0002-7792-1698)
- Brian A. Gordon (ORCID: https://orcid.org/0000-0003-2109-2955)
- Jorge J. Llibre‐Guerra (ORCID: https://orcid.org/0000-0002-2137-7750)
- Haiyan Liu (ORCID: https://orcid.org/0000-0002-3154-8285)
- John C. Morris (ORCID: https://orcid.org/0000-0001-9820-5618)
- Jigyasha Timsina (ORCID: https://orcid.org/0000-0003-4794-9187)
- Christoph Laske
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Pittsburgh (US)
- Washington University in St. Louis (US)
- Brown University (US)
- Korea University Medical Center (KR)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- Butler Hospital (US)
- LMU Klinikum (DE)
- UNSW Sydney (AU)
- Universidad de Antioquia (CO)
- Massachusetts General Hospital (US)
- Munich Cluster for Systems Neurology (DE)
- UK Dementia Research Institute (GB)
- Hertie Institute for Clinical Brain Research (DE)
- Mayo Clinic in Florida (US)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- Niigata University (JP)
- The University of Tokyo (JP)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
- Neuroscience Research Australia (AU)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1002/alz.70243
- Citations
- 4
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.66
Funders
- Alzheimer's Association
- Institute of Clinical and Translational Sciences
- Hope Center for Neurological Disorders
- National Institutes of Health
- National Center for Advancing Translational Sciences