{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:05:50Z","timestamp":1789049150738,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is characterized by progressive neurodegeneration driven by interconnected mechanisms, including oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and abnormal protein aggregation. MicroRNAs (miRNAs) have emerged as post-transcriptional regulators of these complex pathways; however, efficient delivery remains a major limitation. Small extracellular vesicles (sEVs) have been proposed as biologically compatible carriers for miRNA delivery. Methods: In this study, milk-derived sEVs were isolated, characterized, and loaded with microRNA-137-5p (miR-137-5p). Their effects were evaluated in an amyloid-\u03b2 (A\u03b2)-induced in vitro AD model using SH-SY5Y human neuroblastoma cells. Oxidative stress markers, including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), lactate dehydrogenase (LDH), and glutathione peroxidase 1 (GPX1), were assessed. Inflammation- and neuroprotection-related gene expression analyses included intercellular adhesion molecule 1 (ICAM1), tumor necrosis factor alpha (TNF-\u03b1), and brain-derived neurotrophic factor (BDNF). Cytoskeletal injury was evaluated using neurofilament light chain (NfL). Mitochondrial stress markers included cytochrome c (Cyt-c), 8-hydroxy-2\u2032-deoxyguanosine (8-OHdG), PTEN-induced kinase 1 (PINK1), dynamin-1-like protein (DNM1L), and mitochondrial transcription factor A (TFAM). Synaptic and extracellular matrix-associated proteins, including complexin-2 (CPLX2), SPARC-related modular calcium-binding protein 1 (SMOC1), and receptor tyrosine kinase-like orphan receptor 1 (ROR1), as well as AD-related biomarkers, including total tau, phosphorylated tau at threonine 181 (pTau-181), phosphorylated tau at threonine 217 (pTau-217), and amyloid-\u03b2 1\u201340 (A\u03b21\u201340), were evaluated using molecular and biochemical approaches. Results: A\u03b2 exposure was associated with increased oxidative stress, inflammatory activation, mitochondrial and cytoskeletal alterations, synaptic-related disturbances, and elevations in tau- and amyloid-associated proteins. Treatment with unloaded sEVs was associated with partial modulation of several parameters, whereas miR-137-5p-loaded sEVs were consistently associated with normalization of multiple pathological markers toward control levels. Conclusions: These findings indicate that miR-137-5p-enriched sEVs may represent a useful experimental platform for multi-target modulation of AD-related cellular alterations. Further mechanistic and in vivo studies are required to clarify translational relevance.<\/jats:p>","DOI":"10.3390\/pharmaceutics18020251","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T11:45:58Z","timestamp":1771415158000},"page":"251","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["miR-137-5p-Loaded Milk-Derived Small Extracellular Vesicles Modulate Oxidative Stress, Mitochondrial Dysfunction, and Neuroinflammatory Responses in an In Vitro Alzheimer\u2019s Disease Model"],"prefix":"10.3390","volume":"18","author":[{"given":"Sinan","family":"G\u00f6n\u00fcll\u00fc","sequence":"first","affiliation":[{"name":"Department of Neurology, Bursa City Hospital, 16250 Bursa, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5640-3363","authenticated-orcid":false,"given":"\u015eeyma","family":"Ayd\u0131n","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Veterinary Medicine, Atat\u00fcrk University, 25240 Erzurum, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamit","family":"\u00c7elik","sequence":"additional","affiliation":[{"name":"Department of Neurology, Private Buhara Hospital, 25240 Erzurum, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O\u011fuz","family":"\u00c7elik","sequence":"additional","affiliation":[{"name":"Savur Prof. Dr. Aziz Sancar District State Hospital, 47860 Mardin, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sefa","family":"K\u00fc\u00e7\u00fckler","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Veterinary Medicine, Atat\u00fcrk University, 25240 Erzurum, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"Topal","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Faculty of Fisheries, Atat\u00fcrk University, 25240 Erzurum, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramazan","family":"Akay","sequence":"additional","affiliation":[{"name":"Department of Neurology, Eskisehir City Hospital, 26080 Eski\u015fehir, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa Onur","family":"Y\u0131ld\u0131z","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Samsun University, 55060 Samsun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00fclent","family":"Al\u0131m","sequence":"additional","affiliation":[{"name":"Department of Neurology, Private Buhara Hospital, 25240 Erzurum, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7539-0523","authenticated-orcid":false,"given":"Sel\u00e7uk","family":"\u00d6zdemir","sequence":"additional","affiliation":[{"name":"Department of Genetics, Faculty of Veterinary Medicine, Atat\u00fcrk University, 25240 Erzurum, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Dominguez-Gortaire, J., Ruiz, A., Porto-Pazos, A.B., Rodriguez-Yanez, S., and Cedron, F. 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