TY  - JOUR
AU  - Liu, Haiyan
AU  - Bui, Quoc
AU  - Hassenstab, Jason
AU  - Gordon, Brian A
AU  - Benzinger, Tammie L S
AU  - Timsina, Jigyasha
AU  - Sung, Yun Ju
AU  - Karch, Celeste
AU  - Renton, Alan E
AU  - Daniels, Alisha
AU  - Morris, John C
AU  - Xiong, Chengjie
AU  - Ibanez, Laura
AU  - Perrin, Richard J
AU  - Llibre-Guerra, Jorge J
AU  - Day, Gregory S
AU  - Supnet-Bell, Charlene
AU  - Xu, Xiong
AU  - Berman, Sarah B
AU  - Chhatwal, Jasmeer P
AU  - Ikeuchi, Takeshi
AU  - Kasuga, Kensaku
AU  - Niimi, Yoshiki
AU  - Huey, Edward D
AU  - Schofield, Peter R
AU  - Brooks, William S
AU  - Ryan, Natalie S
AU  - Jucker, Mathias
AU  - Laske, Christoph
AU  - Levin, Johannes
AU  - Vöglein, Jonathan
AU  - Roh, Jee Hoon
AU  - Lopera, Francisco
AU  - Bateman, Randall J
AU  - Cruchaga, Carlos
AU  - McDade, Eric M
TI  - Ubiquitin-proteasome system in the different stages of dominantly inherited Alzheimer's disease.
JO  - Alzheimer's and dementia
VL  - 21
IS  - 5
SN  - 1552-5260
CY  - Hoboken, NJ
PB  - Wiley
M1  - DZNE-2025-00648
SP  - e70243
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: cerebrospinal fluid
KW  - Alzheimer Disease: pathology
KW  - Ubiquitin: cerebrospinal fluid
KW  - Proteasome Endopeptidase Complex: cerebrospinal fluid
KW  - Proteasome Endopeptidase Complex: metabolism
KW  - Female
KW  - Male
KW  - Biomarkers: cerebrospinal fluid
KW  - tau Proteins: cerebrospinal fluid
KW  - Disease Progression
KW  - Middle Aged
KW  - Aged
KW  - Mutation: genetics
KW  - Amyloid beta-Peptides: cerebrospinal fluid
KW  - Adult
KW  - amyloid beta (Other)
KW  - amyloid precursor protein (Other)
KW  - autophagy–lysosome pathway (Other)
KW  - biomarker discovery (Other)
KW  - dominantly inherited Alzheimer's disease (Other)
KW  - genetic mutations (Other)
KW  - neurodegeneration (Other)
KW  - presenilin 1 (Other)
KW  - presenilin 2 (Other)
KW  - protein aggregation (Other)
KW  - protein degradation (Other)
KW  - proteomic analysis (Other)
KW  - proteostasis (Other)
KW  - tau pathology (Other)
KW  - ubiquitin–proteasome system (Other)
KW  - Ubiquitin (NLM Chemicals)
KW  - Proteasome Endopeptidase Complex (NLM Chemicals)
KW  - Biomarkers (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40411302
C2  - pmc:PMC12102666
DO  - DOI:10.1002/alz.70243
UR  - https://pub.dzne.de/record/278922
ER  -