{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:54:02Z","timestamp":1785405242449,"version":"3.56.0"},"reference-count":112,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"publisher","award":["R01 AG075992"],"award-info":[{"award-number":["R01 AG075992"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"publisher","award":["R01 AG077636"],"award-info":[{"award-number":["R01 AG077636"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"publisher","award":["R01 AG075069"],"award-info":[{"award-number":["R01 AG075069"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01 AG075992"],"award-info":[{"award-number":["R01 AG075992"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 AG077636"],"award-info":[{"award-number":["R01 AG077636"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01 AG075069"],"award-info":[{"award-number":["R01 AG075069"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tauopathies, including Alzheimer\u2019s disease, involve progressive neurodegeneration and sustained neuroinflammation. We present a multi-compartment transcriptomic atlas of 9.6-month-old PS19 tauopathy mice compared with wild-type (WT) controls (n = 8\/group), profiling cortical mRNA, cortical non-coding RNA (ncRNA), and plasma small extracellular vesicle (pEV) ncRNA. In the PS19 cortex, mRNA sequencing identified 917 differentially expressed genes (DEGs), with microglial deconvolution revealing an association toward disease-associated microglia (DAM) gene signature and downregulation of genes involved in oxidative phosphorylation and cholesterol biosynthesis relative to WT. Cortical ncRNA profiling identified 466 differentially expressed ncRNAs, primarily circular RNAs (circRNAs; n = 331). In pEVs, 822 ncRNAs were differentially abundant, of which 657 circRNAs were identified in PS19 compared to WT mice. Cross-compartment integration suggest that pEV miRNA gene targets functionally mirrored genes involved in the brain\u2019s inflammatory and metabolic failure. We identified a preliminary candidate signature of 33 ncRNAs, including miR-5114 (up in brain, down in pEV), circ_0008242 and circ_0002153 (up in brain and pEV), and circ_0007688 (down in brain and pEV), differentially enriched across both brain and periphery in PS19 compared to WT mice. These results suggest that the pEV non-coding landscape may partially reflect central tau-mediated changes in the brain transcriptional response. This study identifies circRNAs as the most numerically perturbed ncRNA class and provides a foundation for potential peripheral indicators of central brain tau pathology.<\/jats:p>","DOI":"10.3390\/ijms27115050","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:46:48Z","timestamp":1780494408000},"page":"5050","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integration of Transcriptional Signatures from Brain Tissue and Plasma Extracellular Vesicles of a Preclinical Tauopathy Mouse Model"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5794-5174","authenticated-orcid":false,"given":"Tanzima Tarannum","family":"Lucy","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0155-4676","authenticated-orcid":false,"given":"A. N. M.","family":"Mamun-Or-Rashid","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6616-5628","authenticated-orcid":false,"given":"Daniel C.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0249-0280","authenticated-orcid":false,"given":"Iliya","family":"Lefterov","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6761-0984","authenticated-orcid":false,"given":"Radosveta","family":"Koldamova","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6938-6536","authenticated-orcid":false,"given":"Nicholas Francis","family":"Fitz","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1655342","DOI":"10.3389\/fncel.2025.1655342","article-title":"Alzheimer\u2019s disease: Where do we stand now and what are the strategic interventions?","volume":"19","author":"Gonzalez","year":"2025","journal-title":"Front. Cell Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer\u2019s disease: Alzheimer\u2019s Association Workgroup","volume":"20","author":"Jack","year":"2024","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4156","DOI":"10.1007\/s12035-020-02013-1","article-title":"Extracellular Vesicles of Alzheimer\u2019s Disease Patients as a Biomarker for Disease Progression","volume":"57","author":"Aharon","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_4","first-page":"151979","article-title":"Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies?","volume":"2015","year":"2015","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1146\/annurev-pathmechdis-051222-120750","article-title":"Neurodegenerative Disease Tauopathies","volume":"19","author":"Creekmore","year":"2024","journal-title":"Annu. Rev. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2200138","DOI":"10.1002\/bies.202200138","article-title":"Tau, microtubule dynamics, and axonal transport: New paradigms for neurodegenerative disease","volume":"45","author":"Cario","year":"2023","journal-title":"Bioessays"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1007\/BF03345132","article-title":"PRL-secreting pituitary adenomas in pregnancy","volume":"26","author":"Chiodini","year":"2003","journal-title":"J. Endocrinol. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Takeuchi, H., Iba, M., Inoue, H., Higuchi, M., Takao, K., Tsukita, K., Karatsu, Y., Iwamoto, Y., Miyakawa, T., and Suhara, T. (2011). P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021050"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1001\/jamaneurol.2017.2822","article-title":"Kinetics of Human Mutant Tau Prion Formation in the Brains of 2 Transgenic Mouse Lines","volume":"74","author":"Woerman","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.neuron.2007.01.010","article-title":"Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model","volume":"53","author":"Yoshiyama","year":"2007","journal-title":"Neuron"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neurobiolaging.2021.09.006","article-title":"Pathological tau and reactive astrogliosis are associated with distinct functional deficits in a mouse model of tauopathy","volume":"109","author":"Patel","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/s42003-022-03373-1","article-title":"Pathogenic tau recruits wild-type tau into brain inclusions and induces gut degeneration in transgenic SPAM mice","volume":"5","author":"Xia","year":"2022","journal-title":"Commun. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115234","DOI":"10.1016\/j.expneurol.2025.115234","article-title":"Behaviour profile characterization of PS19 and rTg4510 tauopathy mouse models: A systematic review and a meta-analysis","volume":"389","author":"Alves","year":"2025","journal-title":"Exp. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/s41598-023-28081-6","article-title":"Investigation of early molecular alterations in tauopathy with generative adversarial networks","volume":"13","author":"Kim","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41591-018-0223-3","article-title":"Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia","volume":"25","author":"Swarup","year":"2019","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1038\/s41590-018-0259-z","article-title":"A TCR mechanotransduction signaling loop induces negative selection in the thymus","volume":"19","author":"Hong","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/path.6021","article-title":"Circular RNAs: Emerging players in brain aging and neurodegenerative diseases","volume":"259","author":"Wu","year":"2023","journal-title":"J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.tins.2020.07.007","article-title":"Circular RNAs: The Brain Transcriptome Comes Full Circle","volume":"43","author":"Gokool","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s11011-019-00497-y","article-title":"Profiling of differentially expressed circular RNAs in peripheral blood mononuclear cells from Alzheimer\u2019s disease patients","volume":"35","author":"Li","year":"2020","journal-title":"Metab. Brain Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Atrian, F., Ramirez, P., De Mange, J., Marquez, M., Gonzalez, E.M., Minaya, M., Karch, C.M., and Frost, B. (2024). m6A-dependent circular RNA formation mediates tau-induced neurotoxicity. bioRxiv.","DOI":"10.1101\/2024.01.25.577211"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1038\/s41580-021-00419-w","article-title":"Tau oligomers are linked to m(6)A-RNA","volume":"22","author":"Baumann","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pan, R., Chen, D., Hou, L., Hu, R., and Jiao, Z. (2023). Small extracellular vesicles: A novel drug delivery system for neurodegenerative disorders. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1184435"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107890","DOI":"10.1016\/j.phrs.2025.107890","article-title":"Extracellular vesicles: A new frontier in deciphering the mechanisms of traditional Chinese medicine","volume":"219","author":"Wang","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Salim, M.W., Zhang, W., Collins-Praino, L., Wang, Y., and Care, A. (2026). Small Extracellular Vesicles from Neural Cells: Physiological and Pathological Roles, and Potential in Neurodegenerative Therapy. Adv. Healthc. Mater., e04608.","DOI":"10.1002\/adhm.202504608"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"796","DOI":"10.4103\/1673-5374.268893","article-title":"Exosomes as mediators of neuron-glia communication in neuroinflammation","volume":"15","author":"Pascual","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e70470","DOI":"10.1111\/acel.70470","article-title":"Serum-Derived Extracellular Vesicles as Biological Indicator of Mobility Resilience in Older Adults","volume":"25","author":"Fitz","year":"2026","journal-title":"Aging Cell"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Fitz, N.F., Alam, M.S., Ostach, M.A., Garg, S., Lefterov, I., and Koldamova, R. (2026). A novel technique for monitoring Alzheimer\u2019s disease associated changes in brain-derived extracellular vesicle cargos in mouse models. bioRxiv.","DOI":"10.64898\/2026.03.13.711599"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cavanaugh, C.A., Moore, A.E., Fitz, N.F., Lefterov, I., and Koldamova, R. (2025). Transcriptomic Response to Neuromuscular Electrical Stimulation in Muscle, Brain, and Plasma EVs in WT and Klotho-Deficient Mice. Int. J. Mol. Sci., 26.","DOI":"10.1101\/2025.07.25.666815"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105481","DOI":"10.1016\/j.nbd.2021.105481","article-title":"Small nucleolar RNAs in plasma extracellular vesicles and their discriminatory power as diagnostic biomarkers of Alzheimer\u2019s disease","volume":"159","author":"Fitz","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4952","DOI":"10.1002\/alz.13055","article-title":"MicroRNA expression in extracellular vesicles as a novel blood-based biomarker for Alzheimer\u2019s disease","volume":"19","author":"Kumar","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e161987","DOI":"10.1172\/JCI161987","article-title":"Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer\u2019s disease-related mouse models","volume":"133","author":"Dutta","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112785","DOI":"10.1016\/j.celrep.2023.112785","article-title":"Multi-transcriptomics reveals brain cellular responses to peripheral infection in Alzheimer\u2019s disease model mice","volume":"42","author":"Lu","year":"2023","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3416","DOI":"10.1038\/s41467-021-23762-0","article-title":"Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer\u2019s disease","volume":"12","author":"Fitz","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8868","DOI":"10.1038\/s41598-018-27293-5","article-title":"Brain Cell Type Specific Gene Expression and Co-expression Network Architectures","volume":"8","author":"McKenzie","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1038\/s41593-019-0491-3","article-title":"Single-cell transcriptomic profiling of the aging mouse brain","volume":"22","author":"Ximerakis","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.cell.2018.06.021","article-title":"Molecular Architecture of the Mouse Nervous System","volume":"174","author":"Zeisel","year":"2018","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1126\/science.aaa1934","article-title":"Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq","volume":"347","author":"Zeisel","year":"2015","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"11929","DOI":"10.1523\/JNEUROSCI.1860-14.2014","article-title":"An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex","volume":"34","author":"Zhang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1002\/glia.23678","article-title":"Transcriptional regulation of homeostatic and disease-associated-microglial genes by IRF1, LXRbeta, and CEBPalpha","volume":"67","author":"Gao","year":"2019","journal-title":"Glia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40478-020-01099-x","article-title":"Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer\u2019s disease","volume":"9","author":"Sobue","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e20202717","DOI":"10.1084\/jem.20202717","article-title":"Microglia in Alzheimer\u2019s disease at single-cell level. Are there common patterns in humans and mice?","volume":"218","author":"Chen","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1038\/s41467-022-29552-6","article-title":"Microglial NF-kappaB drives tau spreading and toxicity in a mouse model of tauopathy","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_45","first-page":"940603","article-title":"Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: Implications for Alzheimer\u2019s disease","volume":"2013","author":"Perry","year":"2013","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.2174\/1570159X18666200525020259","article-title":"The Role of Mitochondrial Impairment in Alzheimer s Disease Neurodegeneration: The Tau Connection","volume":"18","author":"Quntanilla","year":"2020","journal-title":"Curr. Neuropharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41580-023-00576-0","article-title":"Context-specific regulation of extracellular vesicle biogenesis and cargo selection","volume":"24","author":"Dixson","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","first-page":"80","article-title":"Isolation and analysis methods of extracellular vesicles (EVs)","volume":"2","author":"Zhao","year":"2021","journal-title":"Extracell. Vesicles Circ. Nucl. Acids"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e12352","DOI":"10.1002\/jev2.12352","article-title":"Differential proteomics argues against a general role for CD9, CD81 or CD63 in the sorting of proteins into extracellular vesicles","volume":"12","author":"Fan","year":"2023","journal-title":"J. Extracell. Vesicles"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Simon, M., Fan, Y., Acloque, H., Rubinstein, E., and Burtey, A. (2026). The intercellular transfer of extracellular vesicles markers CD63, CD9 and CD81 is spatially polarized and restricted to cell vicinity. bioRxiv.","DOI":"10.64898\/2026.02.23.707285"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Li, L., Jiang, Y., Wang, J.Z., Liu, R., and Wang, X. (2021). Tau Ubiquitination in Alzheimer\u2019s Disease. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.786353"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11697","DOI":"10.18632\/aging.205057","article-title":"Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model","volume":"15","author":"Cao","year":"2023","journal-title":"Aging"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nn.3975","article-title":"Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity","volume":"18","author":"You","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sun, T., Zeng, L., Cai, Z., Liu, Q., Li, Z., and Liu, R. (2022). Comprehensive analysis of dysregulated circular RNAs and construction of a ceRNA network involved in the pathology of Alzheimer\u2019s disease in a 5 x FAD mouse model. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.1020699"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gonullu, S., Aydin, S., Celik, H., Celik, O., Kucukler, S., Topal, A., Akay, R., Yildiz, M.O., Alim, B., and Ozdemir, S. (2026). Milk-derived miR-126-3p-loaded small extracellular vesicles attenuate amyloid-beta-induced cellular stress in a neuroblastoma cell model. BMC Neurosci., 27.","DOI":"10.1186\/s12868-026-01002-9"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4763","DOI":"10.1093\/cercor\/bhab515","article-title":"miRNA-126a-3p participates in hippocampal memory via alzheimer\u2019s disease-related proteins","volume":"32","author":"Xue","year":"2022","journal-title":"Cereb. Cortex"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107132","DOI":"10.1016\/j.nbd.2025.107132","article-title":"Comparison of neuron-derived extracellular vesicles miRNA profile between patients with behavioural variant frontotemporal dementia and primary psychiatric disorders","volume":"216","author":"Giudici","year":"2025","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3233\/JAD-215223","article-title":"Cerebrovascular microRNA Expression Profile During Early Development of Alzheimer\u2019s Disease in a Mouse Model","volume":"85","author":"Chum","year":"2022","journal-title":"J. Alzheimers Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.devcel.2008.07.002","article-title":"The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis","volume":"15","author":"Wang","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18103\/mra.v8i5.2133","article-title":"An integrated hypothesis for miR-126 in vascular disease","volume":"8","author":"Yu","year":"2020","journal-title":"Med. Res. Arch."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s13105-024-01017-y","article-title":"MicroRNA-126 (MiR-126): Key roles in related diseases","volume":"80","author":"Liao","year":"2024","journal-title":"J. Physiol. Biochem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"102306","DOI":"10.1016\/j.pneurobio.2022.102306","article-title":"Microglia: Friend and foe in tauopathy","volume":"216","author":"Odfalk","year":"2022","journal-title":"Prog. Neurobiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1093\/hmg\/ddp367","article-title":"Tau fragmentation, aggregation and clearance: The dual role of lysosomal processing","volume":"18","author":"Wang","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Guo, M., Hao, Y., Feng, Y., Li, H., Mao, Y., Dong, Q., and Cui, M. (2021). Microglial Exosomes in Neurodegenerative Disease. Front. Mol. Neurosci., 14.","DOI":"10.3389\/fnmol.2021.630808"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e103649","DOI":"10.1002\/alz70855_103649","article-title":"P2RX7 deficiency prevents tau-mediated neurodegeneration via regulation of microglial response and suppression of extracellular vesicles containing tau and toxic mitochondrial content","volume":"21","author":"Santos","year":"2025","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"fcab011","DOI":"10.1093\/braincomms\/fcab011","article-title":"Distinct microglial response against Alzheimer\u2019s amyloid and tau pathologies characterized by P2Y12 receptor","volume":"3","author":"Maeda","year":"2021","journal-title":"Brain Commun."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Lam, M., Kuo, S.Y., Reis, S., Gestwicki, J.E., Silva, M.C., and Haggarty, S.J. (2023). Cholesterol Dysregulation Drives Seed-Dependent Tau Aggregation in Patient Stem Cell-Derived Models of Tauopathy. bioRxiv.","DOI":"10.1101\/2023.12.11.571147"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1038\/s12276-024-01273-4","article-title":"Cholesterol imbalance and neurotransmission defects in neurodegeneration","volume":"56","author":"Shin","year":"2024","journal-title":"Exp. Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Arenas, F., Garcia-Ruiz, C., and Fernandez-Checa, J.C. (2017). Intracellular Cholesterol Trafficking and Impact in Neurodegeneration. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00382"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Raut, S., Bhalerao, A., Powers, M., Gonzalez, M., Mancuso, S., and Cucullo, L. (2023). Hypometabolism, Alzheimer\u2019s Disease, and Possible Therapeutic Targets: An Overview. Cells, 12.","DOI":"10.3390\/cells12162019"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Wang, S., Ponnusamy, M., Patel, O., Hansen, M., Collier, L., Collier, S., and Thinakaran, G. (2025). Spatiotemporal transcriptomic profiling reveals metabolic dysfunction prior to overt tauopathy in the PS19 mouse model. Res. Sq.","DOI":"10.1038\/s12276-026-01652-z"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41398-025-03787-5","article-title":"The emerging role of circular RNAs in neuropsychiatric disorders","volume":"16","author":"Huang","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1038\/s41386-025-02121-3","article-title":"Circular RNAs as a novel player in synaptic transmission and neuropsychiatric disorders","volume":"50","author":"Olcay","year":"2025","journal-title":"Neuropsychopharmacology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1038\/s41380-025-02925-1","article-title":"Circular RNAs in neurological conditions\u2014Computational identification, functional validation, and potential clinical applications","volume":"30","author":"Hatzimanolis","year":"2025","journal-title":"Mol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1038\/s41380-020-0653-4","article-title":"A psychiatric disease-related circular RNA controls synaptic gene expression and cognition","volume":"25","author":"Zimmerman","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9581369","DOI":"10.1155\/np\/9581369","article-title":"Circular RNAs, miRNAs, and Exosomes: Their Roles and Importance in Amyloid-Beta and Tau Pathologies in Alzheimer\u2019s Disease","volume":"2025","author":"Pala","year":"2025","journal-title":"Neural Plast."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Sekar, S., Cuyugan, L., Adkins, J., Geiger, P., and Liang, W.S. (2018). Circular RNA expression and regulatory network prediction in posterior cingulate astrocytes in elderly subjects. BMC Genom., 19.","DOI":"10.1186\/s12864-018-4670-5"},{"key":"ref_79","first-page":"960","article-title":"Role of circRNA in pathogenesis of Alzheimer\u2019s disease","volume":"47","author":"Shen","year":"2022","journal-title":"Zhong Nan Da Xue Xue Bao Yi Xue Ban"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Kim, Y., Kim, E.K., Chey, Y., Song, M.J., and Jang, H.H. (2023). Targeted Protein Degradation: Principles and Applications of the Proteasome. Cells, 12.","DOI":"10.3390\/cells12141846"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1016\/j.molcel.2025.02.021","article-title":"UbiREAD deciphers proteasomal degradation code of homotypic and branched K48 and K63 ubiquitin chains","volume":"85","author":"Kiss","year":"2025","journal-title":"Mol. Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1089\/ars.2019.7826","article-title":"Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized Proteins In Vivo","volume":"31","author":"Manohar","year":"2019","journal-title":"Antioxid. Redox Signal"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.neuroscience.2018.08.003","article-title":"The Age-dependent Elevation of miR-335-3p Leads to Reduced Cholesterol and Impaired Memory in Brain","volume":"390","author":"Raihan","year":"2018","journal-title":"Neuroscience"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"328","DOI":"10.4103\/1673-5374.317975","article-title":"Extracellular vesicles drive tau spreading in Alzheimer\u2019s disease","volume":"17","author":"Ruan","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/brain\/awaa376","article-title":"Alzheimer\u2019s disease brain-derived extracellular vesicles spread tau pathology in interneurons","volume":"144","author":"Ruan","year":"2021","journal-title":"Brain"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Lo Curto, A., Taverna, S., Costa, M.A., Passantino, R., Augello, G., Adamo, G., Aiello, A., Colomba, P., Zizzo, C., and Zora, M. (2021). Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease. Cells, 10.","DOI":"10.3390\/cells10020356"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Petracci, I., Bellini, S., Goljanek-Whysall, K., Quinlan, L.R., Fiszer, A., Cakmak, A., Njume, C.M., Borroni, B., and Ghidoni, R. (2025). Exploring the Role of microRNAs as Blood Biomarkers in Alzheimer\u2019s Disease and Frontotemporal Dementia. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073399"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Yu, X., Liu, H., Chang, N., Fu, W., Guo, Z., and Wang, Y. (2023). Circular RNAs: New players involved in the regulation of cognition and cognitive diseases. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1097878"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40364-025-00886-9","article-title":"Emerging roles of circular RNAs and enhancer RNAs: New insights into the development and management of neurodegenerative disorders","volume":"14","author":"Ziaei","year":"2026","journal-title":"Biomark. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.7150\/ijms.56457","article-title":"Circular RNAs in stem cell differentiation: A sponge-like role for miRNAs","volume":"18","author":"Zhou","year":"2021","journal-title":"Int. J. Med. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"635","DOI":"10.2174\/011570159X337659241014140824","article-title":"The Role of circRNAs in the Pathological Mechanisms of Alzheimer\u2019s Disease: Potential Biomarkers for Diagnosis","volume":"23","author":"Abuduwaili","year":"2025","journal-title":"Curr. Neuropharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.omtm.2020.05.027","article-title":"Circular RNAs: Promising Molecular Biomarkers of Human Aging-Related Diseases via Functioning as an miRNA Sponge","volume":"18","author":"Ren","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"vbad093","DOI":"10.1093\/bioadv\/vbad093","article-title":"circRNA-sponging: A pipeline for extensive analysis of circRNA expression and their role in miRNA sponging","volume":"3","author":"Hoffmann","year":"2023","journal-title":"Bioinform. Adv."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jbiotec.2016.09.011","article-title":"Circular RNAs are miRNA sponges and can be used as a new class of biomarker","volume":"238","author":"Kulcheski","year":"2016","journal-title":"J. Biotechnol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1002\/jex2.35","article-title":"L1CAM-associated extracellular vesicles: A systematic review of nomenclature, sources, separation, and characterization","volume":"1","author":"Gomes","year":"2022","journal-title":"J. Extracell. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1089\/neu.2018.5898","article-title":"Neuronal Enriched Extracellular Vesicle Proteins as Biomarkers for Traumatic Brain Injury","volume":"36","author":"Karnati","year":"2019","journal-title":"J. Neurotrauma"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"eado6894","DOI":"10.1126\/sciadv.ado6894","article-title":"Blood-derived APLP1(+) extracellular vesicles are potential biomarkers for the early diagnosis of brain diseases","volume":"11","author":"Choi","year":"2025","journal-title":"Sci. Adv."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e12459","DOI":"10.1002\/jev2.12459","article-title":"Single-extracellular vesicle (EV) analyses validate the use of L1 Cell Adhesion Molecule (L1CAM) as a reliable biomarker of neuron-derived EVs","volume":"13","author":"Eren","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Mustapic, M., Eitan, E., Werner, J.K., Berkowitz, S.T., Lazaropoulos, M.P., Tran, J., Goetzl, E.J., and Kapogiannis, D. (2017). Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes. Front. Neurosci., 11.","DOI":"10.3389\/fnins.2017.00278"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s40035-024-00453-6","article-title":"Extracellular vesicles: Biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases","volume":"13","author":"Wang","year":"2024","journal-title":"Transl. Neurodegener."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Yu, Y., Wang, Z., Chai, Z., Ma, S., Li, A., and Li, Y. (2025). Central Nervous System-Derived Extracellular Vesicles as Biomarkers in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178272"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkz114","article-title":"The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"gkaf018","DOI":"10.1093\/nar\/gkaf018","article-title":"edgeR v4: Powerful differential analysis of sequencing data with expanded functionality and improved support for small counts and larger datasets","volume":"53","author":"Chen","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Bader, G.D., and Hogue, C.W. (2003). An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform., 4.","DOI":"10.1186\/1471-2105-4-2"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Torres-Oliva, M., Almudi, I., McGregor, A.P., and Posnien, N. (2016). A robust (re-)annotation approach to generate unbiased mapping references for RNA-seq-based analyses of differential expression across closely related species. BMC Genom., 17.","DOI":"10.1186\/s12864-016-2646-x"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1261\/rna.043687.113","article-title":"circBase: A database for circular RNAs","volume":"20","author":"Glazar","year":"2014","journal-title":"RNA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"eaav1741","DOI":"10.1126\/science.aav1741","article-title":"The biochemical basis of microRNA targeting efficacy","volume":"366","author":"McGeary","year":"2019","journal-title":"Science"},{"key":"ref_111","unstructured":"The R Core Team (2026, April 26). R: A Language and Environment for Statistical Computing. Available online: https:\/\/cran.r-project.org\/doc\/manuals\/r-release\/fullrefman.pdf."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1038\/s41598-019-40167-8","article-title":"New Statistical Methods for Constructing Robust Differential Correlation Networks to characterize the interactions among microRNAs","volume":"9","author":"Yu","year":"2019","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5050\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:49:45Z","timestamp":1780494585000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5050"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":112,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27115050"],"URL":"https:\/\/doi.org\/10.3390\/ijms27115050","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]}}}