{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:11:10Z","timestamp":1792019470514,"version":"4.4.0"},"reference-count":119,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Neuroscience \u201cRita Levi-Montalcini\u201d, University of Torino"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a critical deubiquitinating enzyme that is highly expressed in the central nervous system, where it participates in protein degradation and turnover as part of the ubiquitin\u2013proteasome system (UPS). Convincing evidence supports the role of UCH-L1 dysfunction in several neurodegenerative disorders, given its unique position at the crossroad of several aetiopathogenic pathways, including those implicated in Alzheimer\u2019s disease (AD) onset. Indeed, UCH-L1 depletion correlates with decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2), with consequent effects on neuroinflammation. Notably, UCH-L1 can affect the level of phosphorylated tau protein, thus contributing to the formation of neurofibrillary tangles (NFTs). In addition, UCH-L1 influences \u03b2-Secretase 1 (BACE1) expression, resulting in the abnormal accumulation of amyloid-\u03b2 plaques in brain parenchyma. These findings underline UCH-L1\u2019s centrality in maintaining the homeostasis of protein folding and aggregation, which are significantly impaired in AD and AD-related dementias. Given these assumptions, UCH-L1 is recognized as a potential biomarker for AD, highlighting its relevance in governing the fate of crucial pathological mediators of cognitive impairment and neurodegeneration. Herein, we contextualize the involvement of UCH-L1 in different dementia-associated pathways and summarize the state of the art of UCH-L1 as a biomarker for AD diagnosis.<\/jats:p>","DOI":"10.3390\/ijms26189012","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:59:51Z","timestamp":1758088791000},"page":"9012","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["UCH-L1 in Alzheimer\u2019s Disease: A Crucial Player in Dementia-Associated Mechanisms"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6828-356X","authenticated-orcid":false,"given":"Elisa","family":"Porchietto","sequence":"first","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"},{"name":"Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Morello","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"},{"name":"Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Cicilese","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"},{"name":"Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6074-9628","authenticated-orcid":false,"given":"Innocenzo","family":"Rainero","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Rubino","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2817-2835","authenticated-orcid":false,"given":"Elena","family":"Tamagno","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"},{"name":"Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1610-1917","authenticated-orcid":false,"given":"Silvia","family":"Boschi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Guglielmotto","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Torino, Via Cherasco 15, 10126 Torino, Italy"},{"name":"Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Regione Gonzole 10, Orbassano, 10043 Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101078","DOI":"10.1016\/j.arr.2020.101078","article-title":"Ubiquitin biology in neurodegenerative disorders: From impairment to therapeutic strategies","volume":"61","author":"Kumar","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/s41419-023-06183-3","article-title":"The mechanism of linear ubiquitination in regulating cell death and correlative diseases","volume":"14","author":"Gao","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nrd.2017.152","article-title":"Deubiquitylating enzymes and drug discovery: Emerging opportunities","volume":"17","author":"Harrigan","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ramirez, J., Prieto, G., Olazabal-Herrero, A., Borr\u00e0s, E., Fernandez-Vigo, E., Alduntzin, U., Osinalde, N., Beaskoetxea, J., Lectez, B., and Aloria, K. (2021). A Proteomic Approach for Systematic Mapping of Substrates of Human Deubiquitinating Enzymes. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094851"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Snyder, N.A., and Silva, G.M. (2021). Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.101077"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1126\/science.2530630","article-title":"The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase","volume":"246","author":"Wilkinson","year":"1989","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/cbf.3527","article-title":"Hermanowicz, Ubiquitin carboxy-terminal hydrolase L1-physiology and pathology","volume":"38","author":"Matuszczak","year":"2020","journal-title":"Cell Biochem. Funct."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1080\/14728222.2017.1321635","article-title":"Ubiquitin C-terminal hydrolase-L1 (UCH-L1) as a therapeutic and diagnostic target in neurodegeneration, neurotrauma and neuro-injuries","volume":"21","author":"Wang","year":"2017","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/s13041-022-00935-6","article-title":"Distribution of five clinically important neuroglial proteins in the human brain","volume":"15","author":"Kultima","year":"2022","journal-title":"Mol. Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"123","DOI":"10.3892\/ol.2023.13709","article-title":"Ubiquitin C-terminal hydrolase-L1: A new cancer marker and therapeutic target with dual effects (Review)","volume":"25","author":"Wang","year":"2023","journal-title":"Oncol. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1042\/BCJ20160082","article-title":"Ubiquitin C-Terminal hydrolase L1 (UCH-L1): Structure, distribution and roles in brain function and dysfunction","volume":"473","author":"Bishop","year":"2016","journal-title":"Biochem. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Puri, S., and Hsu, S.-T.D. (2024). Functional dynamics of human ubiquitin C-terminal hydrolases. Front. Biophys., 2.","DOI":"10.3389\/frbis.2024.1479898"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"36140","DOI":"10.1074\/jbc.M114.557124","article-title":"The Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) C Terminus Plays a Key Role in Protein Stability, but Its Farnesylation Is Not Required for Membrane Association in Primary Neurons","volume":"289","author":"Bishop","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2756068","DOI":"10.1155\/2016\/2756068","article-title":"It Is All about (U)biquitin: Role of Altered Ubiquitin-Proteasome System and UCHL1 in Alzheimer Disease","volume":"2016","author":"Tramutola","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4675","DOI":"10.1073\/pnas.0510403103","article-title":"Structural basis for conformational plasticity of the Parkinson\u2019s disease-associated ubiquitin hydrolase UCH-L1","volume":"103","author":"Das","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7747","DOI":"10.1007\/s12035-025-04739-2","article-title":"Roles of Ubiquitin Ligases and Deubiquitylases in Alzheimer\u2019s Disease","volume":"62","author":"Jia","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4635","DOI":"10.1073\/pnas.0806474106","article-title":"Membrane-associated farnesylated UCH-L1 promotes \u03b1-synuclein neurotoxicity and is a therapeutic target for Parkinson\u2019s disease","volume":"106","author":"Liu","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1002\/prca.201100068","article-title":"Analysis of a membrane-enriched proteome from postmortem human brain tissue in Alzheimer\u2019s disease","volume":"6","author":"Donovan","year":"2012","journal-title":"Proteom. Clin. Appl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101856","DOI":"10.1016\/j.arr.2023.101856","article-title":"Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury","volume":"86","author":"Mi","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/S0891-5849(02)00914-0","article-title":"Proteomic identification of oxidatively modified proteins in alzheimer\u2019s disease brain. part I: Creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1","volume":"33","author":"Castegna","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13256","DOI":"10.1074\/jbc.M314124200","article-title":"Oxidative Modifications and Down-regulation of Ubiquitin Carboxyl-terminal Hydrolase L1 Associated with Idiopathic Parkinson\u2019s and Alzheimer\u2019s Diseases","volume":"279","author":"Choi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/j.neurobiolaging.2005.09.021","article-title":"Redox proteomics identification of oxidized proteins in Alzheimer\u2019s disease hippocampus and cerebellum: An approach to understand pathological and biochemical alterations in AD","volume":"27","author":"Sultana","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3233\/JAD-2006-10407","article-title":"Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer\u2019s disease: An initial assessment","volume":"10","author":"Butterfield","year":"2006","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaaw0843","DOI":"10.1126\/science.aaw0843","article-title":"Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer\u2019s disease","volume":"371","author":"Nakamura","year":"2021","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6835","DOI":"10.1073\/pnas.1002295107","article-title":"Cyclopentenone prostaglandin-induced unfolding and aggregation of the Parkinson disease-associated UCH-L1","volume":"107","author":"Koharudin","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"887","DOI":"10.2131\/jts.40.887","article-title":"Mercuration of ubiquitin carboxyl-terminal hydrolase L1 through Cys152 by methylmercury causes inhibition of its catalytic activity and reduction of monoubiquitin levels in SH-SY5Y cells","volume":"40","author":"Toyama","year":"2015","journal-title":"J. Toxicol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.neures.2006.04.006","article-title":"Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer\u2019s disease in Colombia","volume":"55","author":"Forero","year":"2006","journal-title":"Neurosci. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.brainres.2006.02.121","article-title":"Genetic association between Ubiquitin Carboxy-terminal Hydrolase-L1 gene S18Y polymorphism and sporadic Alzheimer\u2019s disease in a Chinese Han population","volume":"1087","author":"Xue","year":"2006","journal-title":"Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1750-1326-5-11","article-title":"Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer\u2019s disease","volume":"5","author":"Zetterberg","year":"2010","journal-title":"Mol. Neurodegener."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S0092-8674(02)01012-7","article-title":"The UCH-L1 Gene Encodes Two Opposing Enzymatic Activities that Affect-Synuclein Degradation and Parkinson\u2019s Disease Susceptibility","volume":"111","author":"Liu","year":"2002","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.neuint.2007.05.007","article-title":"The functions of UCH-L1 and its relation to neurodegenerative diseases","volume":"51","author":"Setsuie","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Bdarneh, A., Maniv, I., and Glickman, M.H. (2025). Ubiquitin C-Terminal Hydrolase L1 (UCHL1), Beyond Hydrolysis. BioEssays, 47.","DOI":"10.1002\/bies.70028"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1073\/pnas.1222732110","article-title":"Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration","volume":"110","author":"Bilguvar","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1093\/hmg\/ddg211","article-title":"Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron","volume":"12","author":"Osaka","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.1021\/bi972274d","article-title":"Substrate Specificity of Deubiquitinating Enzymes: Ubiquitin C-Terminal Hydrolases","volume":"37","author":"Larsen","year":"1998","journal-title":"Biochemistry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.279.5348.242","article-title":"Frameshift Mutants of \u03b2 Amyloid Precursor Protein and Ubiquitin-B in Alzheimer\u2019s and Down Patients","volume":"279","author":"Neubauer","year":"1998","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5922","DOI":"10.1038\/s41467-023-41545-7","article-title":"Altered ubiquitin signaling induces Alzheimer\u2019s disease-like hallmarks in a three-dimensional human neural cell culture model","volume":"14","author":"Maniv","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1186\/s40001-025-02886-9","article-title":"Pathological mechanisms and treatment progression of Alzheimer\u2019s disease","volume":"30","author":"Zhang","year":"2025","journal-title":"Eur. J. Med. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2006.06.046","article-title":"Ubiquitin Hydrolase Uch-L1 Rescues \u03b2-Amyloid-Induced Decreases in Synaptic Function and Contextual Memory","volume":"126","author":"Gong","year":"2006","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhang, M., Cai, F., Zhang, S., Zhang, S., and Song, W. (2014). Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer\u2019s progression in vivo. Sci. Rep., 4.","DOI":"10.1038\/srep07298"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/j.1474-9726.2012.00854.x","article-title":"A\u03b21-42-mediated down-regulation of Uch-L1 is dependent on NF-\u03baB activation and impaired BACE1 lysosomal degradation","volume":"11","author":"Guglielmotto","year":"2012","journal-title":"Aging Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16937","DOI":"10.1074\/jbc.M113.463711","article-title":"\u03b2-Amyloid (A\u03b2) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase, UCH-L1","volume":"288","author":"Poon","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1267\/ahc.24-00025","article-title":"Integrated Spatial Multi-Omics Study of Postmortem Brains of Alzheimer\u2019s Disease","volume":"57","author":"Toyama","year":"2024","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0006-8993(95)00729-A","article-title":"Axonal degeneration promotes abnormal accumulation of amyloid \u03b2-protein in ascending gracile tract of gracile axonal dystrophy (GAD) mouse","volume":"695","author":"Ichihara","year":"1995","journal-title":"Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1750-1326-2-22","article-title":"The Alzheimer\u2019s disease Beta-secretase enzyme","volume":"2","author":"Cole","year":"2007","journal-title":"BACE1 Mol. Neurodegener."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"280","DOI":"10.4161\/cam.5.4.16986","article-title":"The roles of amyloid precursor protein (APP) in neurogenesis","volume":"5","author":"Zhou","year":"2011","journal-title":"Cell Adhes. Migr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1096\/fj.04-1994fje","article-title":"Degradation of BACE by the ubiquitin-proteasome pathway","volume":"18","author":"Qing","year":"2004","journal-title":"FASEB J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1111\/j.1471-4159.2011.07644.x","article-title":"Control of BACE1 degradation and APP processing by ubiquitin carboxyl-terminal hydrolase L1","volume":"120","author":"Zhang","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Guglielmotto, M., Monteleone, D., Vasciaveo, V., Repetto, I.E., Manassero, G., Tabaton, M., and Tamagno, E. (2017). The decrease of Uch-L1 activity is a common mechanism responsible for A\u03b2 42 accumulation in Alzheimer\u2019s and vascular disease. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00320"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1111\/j.1471-4159.2011.07172.x","article-title":"NF-\u03baB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression","volume":"116","author":"Wang","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1152\/physrev.00024.2003","article-title":"Role of Tau Protein in Both Physiological and Pathological Conditions","volume":"84","author":"Avila","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Jiang, G., Xie, G., Li, X., and Xiong, J. (2025). Cytoskeletal Proteins and Alzheimer\u2019s Disease Pathogenesis: Focusing on the Interplay with Tau Pathology. Biomolecules, 15.","DOI":"10.3390\/biom15060831"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1111\/j.1755-5949.2010.00177.x","article-title":"The Role of Tau in Alzheimer\u2019s Disease and Related Disorders","volume":"17","author":"Medeiros","year":"2011","journal-title":"CNS Neurosci. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12974-023-02853-3","article-title":"Tau and neuroinflammation in Alzheimer\u2019s disease: Interplay mechanisms and clinical translation","volume":"20","author":"Chen","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.2147\/IJN.S200490","article-title":"Alzheimer\u2019s disease: Pathogenesis, diagnostics, and therapeutics","volume":"14","author":"Tiwari","year":"2019","journal-title":"Int. J. Nanomed."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1042\/BJ20060463","article-title":"Phosphorylation inhibits turnover of the tau protein by the proteasome: Influence of RCAN1 and oxidative stress","volume":"400","author":"Poppek","year":"2006","journal-title":"Biochem. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3233\/JAD-150032","article-title":"UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein","volume":"49","author":"Xie","year":"2015","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jprot.2016.03.022","article-title":"Identification of proteins that are differentially expressed in brains with Alzheimer\u2019s disease using iTRAQ labeling and tandem mass spectrometry","volume":"139","author":"Minjarez","year":"2016","journal-title":"J. Proteom."},{"key":"ref_59","first-page":"3812","article-title":"UCH-L1 Inhibition Suppresses tau Aggresome Formation during Proteasomal Impairment","volume":"55","author":"Yu","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.neuroscience.2014.06.013","article-title":"MicroRNA-922 promotes tau phosphorylation by downregulating ubiquitin carboxy-terminal hydrolase L1 (UCHL1) expression in the pathogenesis of Alzheimer\u2019s disease","volume":"275","author":"Zhao","year":"2014","journal-title":"Neuroscience"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6011","DOI":"10.1021\/ac400831z","article-title":"Mass spectrometry assessment of ubiquitin carboxyl-terminal hydrolase L1 partitioning between soluble and particulate brain homogenate fractions","volume":"85","author":"Chen","year":"2013","journal-title":"Anal. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.arr.2013.03.002","article-title":"The intersection of amyloid beta and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer\u2019s disease","volume":"12","author":"Crimins","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0092-8674(00)80188-9","article-title":"Ubiquitin C-Terminal Hydrolase Is an Immediate-Early Gene Essential for Long-Term Facilitation in Aplysia","volume":"89","author":"Hegde","year":"1997","journal-title":"Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1056\/NEJMcibr065999","article-title":"The Persistence of Memory","volume":"355","author":"Cookson","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1111\/j.1460-9568.2008.06047.x","article-title":"Reduction in memory in passive avoidance learning, exploratory behaviour and synaptic plasticity in mice with a spontaneous deletion in the ubiquitin C-terminal hydrolase L1 gene","volume":"27","author":"Sakurai","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7857","DOI":"10.1523\/JNEUROSCI.1817-09.2009","article-title":"Regulation of Synaptic Structure by Ubiquitin C-Terminal Hydrolase L1","volume":"29","author":"Cartier","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"122282","DOI":"10.1016\/j.lfs.2023.122282","article-title":"TrkB\/BDNF signaling pathway and its small molecular agonists in CNS injury","volume":"336","author":"Wang","year":"2024","journal-title":"Life Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5978","DOI":"10.1523\/JNEUROSCI.3148-16.2017","article-title":"Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB","volume":"37","author":"Guo","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1073\/pnas.0911516107","article-title":"Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction","volume":"107","author":"Chen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Konsman, J.P. (2022). Cytokines in the Brain and Neuroinflammation: We Didn\u2019t Starve the Fire!. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020140"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/jnc.13607","article-title":"Neuroinflammation: The devil is in the details","volume":"139","author":"DiSabato","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Al-Ghraiybah, N.F., Wang, J., Alkhalifa, A.E., Roberts, A.B., Raj, R., Yang, E., and Kaddoumi, A. (2022). Glial Cell-Mediated Neuroinflammation in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810572"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1177\/0271678X20951995","article-title":"Regulation of blood\u2013brain barrier integrity by microglia in health and disease: A therapeutic opportunity","volume":"40","author":"Ronaldson","year":"2020","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Pasko, V.I., Churkina, A.S., Shakhov, A.S., Kotlobay, A.A., and Alieva, I.B. (2023). Modeling of Neurodegenerative Diseases: \u2018Step by Step\u2019 and \u2018Network\u2019 Organization of the Complexes of Model Systems. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010604"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12987-024-00557-1","article-title":"Cellular and molecular mechanisms of the blood\u2013brain barrier dysfunction in neurodegenerative diseases","volume":"21","author":"Chen","year":"2024","journal-title":"Fluids Barriers CNS"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s41467-018-03509-0","article-title":"A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers","volume":"9","author":"Thibaudeau","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1146\/annurev.bi.61.070192.003553","article-title":"The Ubiquitin system for protein degradation","volume":"61","author":"Hershko","year":"1992","journal-title":"Annu. Rev. Biochem."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Han, D., Zheng, W., Wang, X., and Chen, Z. (2020). Proteostasis of \u03b1-Synuclein and Its Role in the Pathogenesis of Parkinson\u2019s Disease. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.00045"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"149202","DOI":"10.1016\/j.brainres.2024.149202","article-title":"Proteostasis disruption and senescence in Alzheimer\u2019s disease pathways to neurodegeneration","volume":"1845","author":"Thapa","year":"2024","journal-title":"Brain Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"S73","DOI":"10.1002\/ana.10512","article-title":"Schapira, Jenner, Isacson, Hunot, Tatton, Beal, Proteolytic stress: A unifying concept for the etiopathogenesis of Parkinson\u2019s disease","volume":"53","author":"McNaught","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Sonninen, T.M., Goldsteins, G., Laham-Karam, N., Koistinaho, J., and Lehtonen, \u0160. (2020). Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases. Cells, 9.","DOI":"10.3390\/cells9102183"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1074\/mcp.RA118.000835","article-title":"Proteomic Analysis of Hippocampus in a Mouse Model of Depression Reveals Neuroprotective Function of Ubiquitin C-terminal Hydrolase L1 (UCH-L1) via Stress-induced Cysteine Oxidative Modifications","volume":"17","author":"Choi","year":"2018","journal-title":"Mol. Cell. Proteom."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Puri, S., and Hsu, S.T.D. (2021). Cross-over Loop Cysteine C152 Acts as an Antioxidant to Maintain the Folding Stability and Deubiquitinase Activity of UCH-L1 Under Oxidative Stress. J. Mol. Biol., 433.","DOI":"10.1016\/j.jmb.2021.166879"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1046\/j.1471-4159.1999.0731660.x","article-title":"Decrease in Peptide Methionine Sulfoxide Reductase in Alzheimer\u2019s Disease Brain","volume":"73","author":"Gabbita","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_85","first-page":"527518","article-title":"Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer\u2019s-Like Neurodegeneration","volume":"2014","author":"Head","year":"2014","journal-title":"Adv. Geriatr."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1111\/j.1745-7254.2007.00741.x","article-title":"Dual roles of NF-\u03baB in cell survival and implications of NF-\u03baB inhibitors in neuroprotective therapy","volume":"28","author":"Qin","year":"2007","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1002\/cbin.11662","article-title":"UCHL1 regulates inflammation via MAPK and NF-\u03baB pathways in LPS-activated macrophages","volume":"45","author":"Zhang","year":"2021","journal-title":"Cell Biol. Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"114152","DOI":"10.1016\/j.celrep.2024.114152","article-title":"Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1\u03b2 production in human macrophages and microglia","volume":"43","author":"Liang","year":"2024","journal-title":"Cell Rep."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.brainresbull.2011.10.004","article-title":"Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases","volume":"87","author":"Smith","year":"2012","journal-title":"Brain Res. Bull."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"907","DOI":"10.3233\/JAD-190494","article-title":"Stroke and Amyloid-\u03b2 Downregulate TREM-2 and Uch-L1 Expression that Synergistically Promote the Inflammatory Response","volume":"71","author":"Guglielmotto","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13024-021-00440-9","article-title":"Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model","volume":"16","author":"Clayton","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Cohn, W., Melnik, M., Huang, C., Teter, B., Chandra, S., Zhu, C., McIntire, L.B., John, V., Gylys, K.H., and Bilousova, T. (2021). Multi-Omics Analysis of Microglial Extracellular Vesicles From Human Alzheimer\u2019s Disease Brain Tissue Reveals Disease-Associated Signatures. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.766082"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1186\/s12974-024-03243-z","article-title":"CX3CR1+\/UCHL1+ microglial extracellular vesicles in blood: A potential biomarker for multiple sclerosis","volume":"21","author":"Duan","year":"2024","journal-title":"J. Neuroinflamm."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/s41582-023-00822-1","article-title":"Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration","volume":"19","author":"Patani","year":"2023","journal-title":"Nat. Rev. Neurol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/s41419-023-06003-8","article-title":"UCHL1 facilitates protein aggregates clearance to enhance neural stem cell activation in spinal cord injury","volume":"14","author":"Ding","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.ajem.2015.05.023","article-title":"Serum ubiquitin C-terminal hydrolase L1 as a biomarker for traumatic brain injury: A systematic review and meta-analysis","volume":"33","author":"Li","year":"2015","journal-title":"Am. J. Emerg. Med."},{"key":"ref_97","unstructured":"U.S. Food and Drug Administration (FDA) (2025, July 14). Evaluation of Automatic Class III Designation for Banyan Brain Trauma Indicator_Decision-Memorandum, Available online: https:\/\/www.accessdata.fda.gov\/cdrh_docs\/reviews\/DEN170045.pdf."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00018-024-05186-3","article-title":"Deubiquitinase UCHL1 promotes angiogenesis and blood\u2013spinal cord barrier function recovery after spinal cord injury by stabilizing Sox17","volume":"81","author":"Wang","year":"2024","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1161\/CIRCRESAHA.118.313316","article-title":"Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier","volume":"124","author":"Corada","year":"2019","journal-title":"Circ. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e14528","DOI":"10.1002\/alz.14528","article-title":"Considerations in the clinical use of amyloid PET and CSF biomarkers for Alzheimer\u2019s disease","volume":"21","author":"Leuzy","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1159\/000447239","article-title":"Increased Cerebrospinal Fluid Levels of Ubiquitin Carboxyl-Terminal Hydrolase L1 in Patients with Alzheimer\u2019s Disease","volume":"6","author":"Johansson","year":"2016","journal-title":"Dement. Geriatr. Cogn. Dis. Extra"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1002\/mds.28738","article-title":"Systematic Assessment of 10 Biomarker Candidates Focusing on \u03b1-Synuclein-Related Disorders","volume":"36","author":"Schulz","year":"2021","journal-title":"Mov. Disord."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12014-020-09285-8","article-title":"Targeted mass spectrometry to quantify brain-derived cerebrospinal fluid biomarkers in Alzheimer\u2019s disease","volume":"17","author":"Zhou","year":"2020","journal-title":"Clin. Proteom."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5096","DOI":"10.1021\/acs.jproteome.4c00590","article-title":"Defining Alzheimer\u2019s Disease through Proteomic CSF Profiling","volume":"23","author":"Balaguer","year":"2024","journal-title":"J. Proteome Res."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Chatziefstathiou, A., Canaslan, S., Kanata, E., Vekrellis, K., Constantinides, V.C., Paraskevas, G.P., Kapaki, E., Schmitz, M., Zerr, I., and Xanthopoulos, K. (2024). SIMOA Diagnostics on Alzheimer\u2019s Disease and Frontotemporal Dementia. Biomedicines, 12.","DOI":"10.3390\/biomedicines12061253"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s13195-023-01269-8","article-title":"Potential diagnostic value of CSF metabolism-related proteins across the Alzheimer\u2019s disease continuum","volume":"15","author":"Paciotti","year":"2023","journal-title":"Alzheimers Res. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Wojda\u0142a, A.L., Bellomo, G., Gaetani, L., Toja, A., Chipi, E., Shan, D., Chiasserini, D., and Parnetti, L. (2023). Trajectories of CSF and plasma biomarkers across Alzheimer\u2019s disease continuum: Disease staging by NF-L, p-tau181, and GFAP. Neurobiol. Dis., 189.","DOI":"10.1016\/j.nbd.2023.106356"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"E860","DOI":"10.1212\/WNL.0000000000201597","article-title":"Diagnostic Performance and Clinical Applicability of Blood-Based Biomarkers in a Prospective Memory Clinic Cohort","volume":"100","author":"Sarto","year":"2023","journal-title":"Neurology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3233\/JAD-231027","article-title":"Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort","volume":"97","author":"Lobue","year":"2024","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/978-1-0716-4462-1_3","article-title":"Application of Single Molecule Array (SIMOA) in Cerebrospinal Fluid","volume":"2914","year":"2025","journal-title":"Methods Mol. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.1002\/alz.12570","article-title":"CSF biomarkers and plasma p-tau181 as predictors of longitudinal tau accumulation: Implications for clinical trial design","volume":"18","author":"Moscoso","year":"2022","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1038\/s41467-020-15436-0","article-title":"Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer\u2019s disease","volume":"11","author":"Janelidze","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13195-020-00596-4","article-title":"Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer\u2019s disease and PET amyloid-positive patient identification","volume":"12","author":"Bateman","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Kawahata, I., Sekimori, T., Oizumi, H., Takeda, A., and Fukunaga, K. (2023). Using Fatty Acid-Binding Proteins as Potential Biomarkers to Discriminate between Parkinson\u2019s Disease and Dementia with Lewy Bodies: Exploration of a Novel Technique. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713267"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.nbd.2005.11.005","article-title":"Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies","volume":"22","author":"Barrachina","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1002\/acn3.51141","article-title":"UCHL1 from serum and CSF is a candidate biomarker for amyotrophic lateral sclerosis","volume":"7","author":"Li","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Mondello, S., Palmio, J., Streeter, J., Hayes, R.L., Peltola, J., and Jeromin, A. (2012). Ubiquitin Carboxy-Terminal Hydrolase L1 (UCH-L1) is increased in cerebrospinal fluid and plasma of patients after epileptic seizure. BMC Neurol., 12.","DOI":"10.1186\/1471-2377-12-85"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.18632\/aging.102695","article-title":"Plasma ubiquitin C-terminal hydrolase L1 levels reflect disease stage and motor severity in Parkinson\u2019s disease","volume":"12","author":"Ng","year":"2020","journal-title":"Aging"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9012\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:46:31Z","timestamp":1760035591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":119,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26189012"],"URL":"https:\/\/doi.org\/10.3390\/ijms26189012","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]}}}