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001     278922
005     20250606100749.0
024 7 _ |a 10.1002/alz.70243
|2 doi
024 7 _ |a pmid:40411302
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024 7 _ |a pmc:PMC12102666
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024 7 _ |a 1552-5260
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024 7 _ |a 1552-5279
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037 _ _ |a DZNE-2025-00648
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Liu, Haiyan
|b 0
245 _ _ |a Ubiquitin-proteasome system in the different stages of dominantly inherited Alzheimer's disease.
260 _ _ |a Hoboken, NJ
|c 2025
|b Wiley
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a 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.
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650 _ 7 |a amyloid beta
|2 Other
650 _ 7 |a amyloid precursor protein
|2 Other
650 _ 7 |a autophagy–lysosome pathway
|2 Other
650 _ 7 |a biomarker discovery
|2 Other
650 _ 7 |a dominantly inherited Alzheimer's disease
|2 Other
650 _ 7 |a genetic mutations
|2 Other
650 _ 7 |a neurodegeneration
|2 Other
650 _ 7 |a presenilin 1
|2 Other
650 _ 7 |a presenilin 2
|2 Other
650 _ 7 |a protein aggregation
|2 Other
650 _ 7 |a protein degradation
|2 Other
650 _ 7 |a proteomic analysis
|2 Other
650 _ 7 |a proteostasis
|2 Other
650 _ 7 |a tau pathology
|2 Other
650 _ 7 |a ubiquitin–proteasome system
|2 Other
650 _ 7 |a Ubiquitin
|2 NLM Chemicals
650 _ 7 |a Proteasome Endopeptidase Complex
|0 EC 3.4.25.1
|2 NLM Chemicals
650 _ 7 |a Biomarkers
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Alzheimer Disease: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Ubiquitin: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Proteasome Endopeptidase Complex: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Proteasome Endopeptidase Complex: metabolism
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Biomarkers: cerebrospinal fluid
|2 MeSH
650 _ 2 |a tau Proteins: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Disease Progression
|2 MeSH
650 _ 2 |a Middle Aged
|2 MeSH
650 _ 2 |a Aged
|2 MeSH
650 _ 2 |a Mutation: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: cerebrospinal fluid
|2 MeSH
650 _ 2 |a Adult
|2 MeSH
700 1 _ |a Bui, Quoc
|b 1
700 1 _ |a Hassenstab, Jason
|b 2
700 1 _ |a Gordon, Brian A
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700 1 _ |a Benzinger, Tammie L S
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700 1 _ |a Timsina, Jigyasha
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700 1 _ |a Sung, Yun Ju
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700 1 _ |a Karch, Celeste
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700 1 _ |a Renton, Alan E
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700 1 _ |a Daniels, Alisha
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700 1 _ |a Morris, John C
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700 1 _ |a Xiong, Chengjie
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700 1 _ |a Ibanez, Laura
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700 1 _ |a Perrin, Richard J
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700 1 _ |a Llibre-Guerra, Jorge J
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700 1 _ |a Day, Gregory S
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700 1 _ |a Supnet-Bell, Charlene
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700 1 _ |a Xu, Xiong
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700 1 _ |a Berman, Sarah B
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700 1 _ |a Chhatwal, Jasmeer P
|b 19
700 1 _ |a Ikeuchi, Takeshi
|b 20
700 1 _ |a Kasuga, Kensaku
|b 21
700 1 _ |a Niimi, Yoshiki
|b 22
700 1 _ |a Huey, Edward D
|b 23
700 1 _ |a Schofield, Peter R
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700 1 _ |a Brooks, William S
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700 1 _ |a Ryan, Natalie S
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700 1 _ |a Vöglein, Jonathan
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700 1 _ |a Roh, Jee Hoon
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700 1 _ |a Lopera, Francisco
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700 1 _ |a Bateman, Randall J
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700 1 _ |a Cruchaga, Carlos
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700 1 _ |a McDade, Eric M
|0 0000-0002-6764-3866
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700 1 _ |a team, For DIAN study
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773 _ _ |a 10.1002/alz.70243
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