ArticleThe Journal of clinical investigation2022
USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation.
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Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed, 62 citations in OpenAlex.
- The deubiquitinase USP25 contributes to stemness and malignant progression of breast cancer by stabilizing C1ql4.Scientific reports · 2026Article
- FBXW7α regulates amyloid pathology by mediating ubiquitination and degradation of BACE1 in Alzheimer's disease.Cell death discovery · 2026Article
- Structure Merging Approach Leads to New Dual Potent and Selective USP25/USP28 Inhibitors.Journal of medicinal chemistry · 2026Article
- USP25 regulates atherosclerosis by restricting RIPK1-mediated inflammatory responses.EBioMedicine · 2026Article
- Use of anti-amyloid-β monoclonal antibodies in persons with Down syndrome Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Review
- Ubiquitin-specific peptidase-19 links TDP-43 aggregation to ER stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- USP25 deficiency suppresses diet-induced obesity via ubiquitination and degradation of PARP1 and Elovl3 downregulation.Journal of lipid research · 2026Article
- USP25 inhibition ameliorates Parkinson's disease by restoring mitophagy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Ubiquitin-specific protease 25: a new regulator for cardiovascular and cerebrovascular diseases.Frontiers in cell and developmental biology · 2026Review
- Endothelial epigenetic senescence driven microglial activation mediates cardio-retinal neuroinflammation in heart failure.Theranostics · 2026Article
- Deubiquitinating enzymes at the crossroads of blood-brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions.Tissue barriers · 2026Review
- Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.Translational neurodegeneration · 2025Review
- Article
- Interferon signaling modulates Down syndrome-associated Alzheimer's disease pathology in a mouse model.iScience · 2025Article
- Roles of Ubiquitin Ligases and Deubiquitylases in Alzheimer's Disease.Molecular neurobiology · 2025Review
- Effects of USP25 knockout on the gut microbial diversity and composition in mice.BMC microbiology · 2025Article
- Article
- Peripheral and central neuroimmune mechanisms in Alzheimer's disease pathogenesis.Molecular neurodegeneration · 2025Review
- Ubiquitin-specific protease 25 improves myocardial ischemia-reperfusion injury by deubiquitinating NLRP3 and negatively regulating NLRP3 inflammasome activity in cardiomyocytes.Clinical and translational medicine · 2025Article
- Alzheimer's disease: insights into pathology, molecular mechanisms, and therapy.Protein & cell · 2025Review
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Authors and funding
30 authors at 6 institutions in 3 countries.
Qiuyang ZhengState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Beibei SongTownsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Guilin LiState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Fang CaiTownsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Meiling WuState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Yingjun ZhaoState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
LuLin JiangNeuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Tiantian GuoState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Mingyu ShenState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Huan HouState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Ying ZhouDepartment of Translational Medicine, School of Medicine, Xiamen University, Xiamen, China.
Yini ZhaoState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Anjie DiState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Lishan ZhangState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Fanwei ZengState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Xiu-Fang ZhangDepartment of Pediatrics, Xiang'an Hospital of Xiamen University, Xiamen, China.
Hong LuoState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Xian ZhangState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Hongfeng ZhangState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Zhiping ZengSchool of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiamen, China.
Timothy Y HuangNeuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
Chen DongInstitute for Immunology, School of Medicine, Tsinghua University, Beijing, China.
Hong QingKey Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China.
Yun ZhangTownsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Qing ZhangTownsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Xu WangInstitute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, School of Mental Health and Kangning Hospital, Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Yili WuInstitute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, School of Mental Health and Kangning Hospital, Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China.
Huaxi XuState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Weihong SongTownsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Xin WangState Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neuroscience, Center for Brain Sciences, First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Xiamen University · CNUniversity of British Columbia · CASanford Burnham Prebys Medical Discovery Institute · USBeijing Institute of Technology · CNTsinghua University · CNWenzhou Medical University · CN
Funding
CIHR PJT-166127
Abstract
Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and Aβ generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.
Indexed as
Alzheimer DiseaseAmyloidosisDown SyndromeAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAmyloid Precursor Protein SecretasesAnimalsAspartic Acid EndopeptidasesBrainDisease Models, AnimalFlavin-Adenine DinucleotideMiceMice, TransgenicUbiquitin ThiolesteraseAmyloid beta-PeptidesAmyloid beta-Protein PrecursorAmyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesFlavin-Adenine DinucleotideUbiquitin ThiolesteraseUSP25 protein, mouseAlzheimer diseaseNeuroscience
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.