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Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease
Shan Jiang, Malavika Srikanth, Rossana Serpe, Shadi Yavari, Pallavi Gaur, Galen Andrew Collins, Rajesh Soni, Vilas Menon et al.. Brain : a journal of neurology, 2025-12-04
Topic: Disease mechanisms in lab and animal studies
Here, we integrated multiple approaches to characterize proteasome function, composition and regulation in post-mortem human AD brain tissue compared with age-matched controls. We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes. Proteomic profiling of isolated proteasomes revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g. tau, α-synuclein and SQSTM1/p62), suggesting proteasome entrapment in pathological aggregates. Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course.
Key findings
- Here, we integrated multiple approaches to characterize proteasome function, composition and regulation in post-mortem human AD brain tissue compared with age-matched controls.
- We found that proteasome activity is significantly impaired in AD brains, affecting both 26S and 20S complexes.
- Proteomic profiling of isolated proteasomes revealed diminished abundances of constitutive proteasome complexes and the co-purification of proteasomes with aggregation-prone substrates (e.g. tau, α-synuclein and SQSTM1/p62), suggesting proteasome entrapment in pathological aggregates.
- Collectively, our findings suggest that proteasome dysfunction in AD arises early and deepens over the disease course.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40488453) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Jiang, S., Srikanth, M., Serpe, R., Yavari, S., Gaur, P., Collins, G. A., et al. (2025). Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease. Brain : a journal of neurology. https://doi.org/10.1093/brain/awaf222
Vancouver
Jiang S, Srikanth M, Serpe R, Yavari S, Gaur P, Collins GA, et al. Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease. Brain : a journal of neurology. 2025. doi:10.1093/brain/awaf222. PMID: 40488453.
BibTeX
@article{jiang2025-40488453,
author = {Jiang, Shan and Srikanth, Malavika and Serpe, Rossana and Yavari, Shadi and Gaur, Pallavi and Collins, Galen Andrew and Soni, Rajesh and Menon, Vilas and others},
title = {{Early proteasome downregulation and dysfunction drive proteostasis failure in Alzheimer's disease}},
journal = {Brain : a journal of neurology},
year = {2025},
doi = {10.1093/brain/awaf222},
pmid = {40488453},
url = {https://doi.org/10.1093/brain/awaf222}
}
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