{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:21:30Z","timestamp":1765516890604,"version":"3.48.0"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2023 Key Scientific Research Platforms"},{"name":"Projects of Guangdong Provincial Universities\u2014Special Program for Key Fields in Guangdong Provincial Universities","award":["2023ZDZX2027"],"award-info":[{"award-number":["2023ZDZX2027"]}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"crossref","award":["2023A1515110780"],"award-info":[{"award-number":["2023A1515110780"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]},{"name":"program for scientific research start-up funds of Guangdong Ocean University","award":["060302122312"],"award-info":[{"award-number":["060302122312"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a common neurodegenerative disorder with limited effective treatments. Cod skin collagen peptides (CSCPs) have neuroprotective potential for AD but face poor bioavailability\u2014due to gastrointestinal enzyme cleavage and hepatic first-pass metabolism\u2014prompting this study to develop a nanodelivery system to enhance CSCPs\u2019 efficacy. Trimethyl chitosan (TMC)-based CSCP-loaded nanoparticles (CSCPs-NPs) were synthesized via ionic gelation, characterized for physicochemical properties, and tested in a D-galactose-induced AD mouse model (six groups: normal control, model, CSCPs low\/high dose, blank NPs, CSCPs-NPs) using behavioral tests, histopathology, immunohistochemistry, and ELISA. CSCPs-NPs had a hydrodynamic diameter of 93.25 \u00b1 21.52 nm, polydispersity index of 0.18 \u00b1 0.13, 61.17% encapsulation efficiency, and sustained 24 h release. In AD mice, CSCPs-NPs significantly improved cognitive function and motor coordination, reduced hippocampal atrophy, preserved neurons, and mitigated oxidative stress, neuroinflammation, and apoptosis (upregulated Bcl-2, downregulated Bax)\u2014effects matching high-dose free CSCPs. This TMC-based nanoformulation enhances CSCPs\u2019 bioavailability and provides a promising strategy for AD intervention.<\/jats:p>","DOI":"10.3390\/md23120472","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T15:32:17Z","timestamp":1765380737000},"page":"472","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trimethyl Chitosan-Engineered Cod Skin Peptide Nanosystems Alleviate Behavioral and Cognitive Deficits in D-Galactose-Induced Alzheimer\u2019s Disease Model Mice"],"prefix":"10.3390","volume":"23","author":[{"given":"Songzhi","family":"Kong","sequence":"first","affiliation":[{"name":"College of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijiao","family":"Lv","sequence":"additional","affiliation":[{"name":"College of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2797-3791","authenticated-orcid":false,"given":"Guiping","family":"Lu","sequence":"additional","affiliation":[{"name":"College of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongdong","family":"Li","sequence":"additional","affiliation":[{"name":"College of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2709-5626","authenticated-orcid":false,"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Chemistry and Environmental Science, Guangdong Ocean University, Zhanjiang 524088, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Alzheimer\u2019s Association (2024). 2024 Alzheimer\u2019s disease facts and figures. Alzheimers Dement., 20, 3708\u20133821.","DOI":"10.1002\/alz.13809"},{"key":"ref_3","unstructured":"GBD 2019 Dementia Forecasting Collaborators (2022). Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019. Lancet Public Health, 7, e105\u2013e125."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e20250965","DOI":"10.1084\/jem.20250965","article-title":"ApoE-calypse tau: ApoE-tau synergy in Alzheimer\u2019s disease","volume":"222","author":"Lennol","year":"2025","journal-title":"J. Exp. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e70404","DOI":"10.1002\/alz.70404","article-title":"An integrated view of the relationships between amyloid, tau, and inflammatory pathophysiology in Alzheimer\u2019s disease","volume":"21","author":"Arnsten","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2198","DOI":"10.1016\/S0140-6736(24)01883-X","article-title":"Passive anti-amyloid \u03b2 immunotherapy in Alzheimer\u2019s disease-opportunities and challenges","volume":"404","author":"Heneka","year":"2024","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/s41392-023-01484-7","article-title":"Amyloid \u03b2-based therapy for Alzheimer\u2019s disease: Challenges, successes and future","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41583-019-0132-6","article-title":"Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease","volume":"20","author":"Butterfield","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2015.12.004","article-title":"Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients","volume":"91","author":"Pupo","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41577-024-01104-7","article-title":"Neuroinflammation in Alzheimer disease","volume":"25","author":"Heneka","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Han, J., Zhang, Z., Zhang, P., Yu, Q., Cheng, Q., Lu, Z., and Zong, S. (2025). The roles of microglia and astrocytes in neuroinflammation of Alzheimer\u2019s disease. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1575453"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155822","DOI":"10.1016\/j.phymed.2024.155822","article-title":"Potential therapeutic natural compounds for the treatment of Alzheimer\u2019s disease","volume":"132","author":"Huang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fakhri, S., Yarmohammadi, A., Yarmohammadi, M., Farzaei, M.H., and Echeverria, J. (2021). Marine Natural Products: Promising Candidates in the Modulation of Gut-Brain Axis towards Neuroprotection. Mar. Drugs, 19.","DOI":"10.3390\/md19030165"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108751","DOI":"10.1016\/j.pharmthera.2024.108751","article-title":"The potential therapeutic strategy in combating neurodegenerative diseases: Focusing on natural products","volume":"264","author":"Gao","year":"2024","journal-title":"Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Jia, C., Chai, J., Zhang, S., Sun, Y., He, L., Sang, Z., Chen, D., and Zheng, X. (2025). The Advancements of Marine Natural Products in the Treatment of Alzheimer\u2019s Disease: A Study Based on Cell and Animal Experiments. Mar. Drugs, 23.","DOI":"10.3390\/md23030091"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8651","DOI":"10.1002\/jsfa.70107","article-title":"Fish scale collagen peptide improves neurodegenerative disorders by dual regulation of acetylcholinesterase activity and antioxidant defense system","volume":"105","author":"Shen","year":"2025","journal-title":"J. Sci. Food Agric."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102177","DOI":"10.1016\/j.arr.2023.102177","article-title":"Bridging neurotrophic factors and bioactive peptides to Alzheimer\u2019s disease","volume":"94","author":"Wei","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"127489","DOI":"10.1016\/j.foodchem.2020.127489","article-title":"Physicochemical and functional properties of Maillard reaction products derived from cod (Gadus morhua L.) skin collagen peptides and xylose","volume":"333","author":"Chen","year":"2020","journal-title":"Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rodrigues, C.V., Sousa, R.O., Carvalho, A.C., Alves, A.L., Marques, C.F., Cerqueira, M.T., Reis, R.L., and Silva, T.H. (2023). Potential of Atlantic Codfish (Gadus morhua) Skin Collagen for Skincare Biomaterials. Molecules, 28.","DOI":"10.3390\/molecules28083394"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7972","DOI":"10.1039\/D5FO02080H","article-title":"Anti-photoaging activity of cod peptides: Structural characterisation and clinical validation","volume":"16","author":"He","year":"2025","journal-title":"Food Funct."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Song, X., Li, Z., Li, Y., and Hou, H. (2022). Typical structure, biocompatibility, and cell proliferation bioactivity of collagen from Tilapia and Pacific cod. Colloids Surf. B Biointerfaces, 210.","DOI":"10.1016\/j.colsurfb.2021.112238"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"419","DOI":"10.2147\/DDDT.S391812","article-title":"Preparation of Cod Skin Collagen Peptides\/Chitosan-Based Temperature-Sensitive Gel and Its Anti-Photoaging Effect in Skin","volume":"17","author":"Kong","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41538-024-00367-7","article-title":"Anti-inflammatory activity of collagen peptide in vitro and its effect on improving ulcerative colitis","volume":"9","author":"Xin","year":"2025","journal-title":"NPJ Sci. Food"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, R., Ren, Y., Ren, T., Yu, Y., Li, B., and Zhou, X. (2025). Marine-Derived Antioxidants: A Comprehensive Review of Their Therapeutic Potential in Oxidative Stress-Associated Diseases. Mar. Drugs, 23.","DOI":"10.3390\/md23060223"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ijbiomac.2022.01.162","article-title":"Recent advances of chitosan-based nanoparticles for biomedical and biotechnological applications","volume":"203","author":"Gao","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.carbpol.2016.10.041","article-title":"N,N,N-Trimethyl chitosan: An advanced polymer with myriad of opportunities in nanomedicine","volume":"157","author":"Kulkarni","year":"2017","journal-title":"Carbohydr. Polym."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119273","DOI":"10.1016\/j.carbpol.2022.119273","article-title":"N-trimethyl chitosan coated targeting nanoparticles improve the oral bioavailability and antioxidant activity of vitexin","volume":"286","author":"Li","year":"2022","journal-title":"Carbohydr. Polym."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yang, J.-M., Wu, L.-J., Lin, M.-T., Lu, Y.-Y., Wang, T.-T., Han, M., Zhang, B., and Xu, D.-H. (2022). Construction and Evaluation of Chitosan-Based Nanoparticles for Oral Administration of Exenatide in Type 2 Diabetic Rats. Polymers, 14.","DOI":"10.3390\/polym14112181"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s10495-023-01848-y","article-title":"Apoptosis in Alzheimer\u2019s disease: Insight into the signaling pathways and therapeutic avenues","volume":"28","author":"Kumari","year":"2023","journal-title":"Apoptosis"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1007\/s11064-014-1454-4","article-title":"Apoptosis in Alzheimer\u2019s disease: An understanding of the physiology, pathology and therapeutic avenues","volume":"39","author":"Obulesu","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.carbpol.2006.10.007","article-title":"A novel method for obtaining a quaternary salt of chitosan","volume":"69","author":"Assis","year":"2007","journal-title":"Carbohydr. Polym."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1007\/BF02974081","article-title":"Research on thymopentin loaded oral N-trimethyl chitosan nanoparticles","volume":"29","author":"Yuan","year":"2006","journal-title":"Arch. Pharm. Res."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/23\/12\/472\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:19:31Z","timestamp":1765516771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/23\/12\/472"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,10]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["md23120472"],"URL":"https:\/\/doi.org\/10.3390\/md23120472","relation":{},"ISSN":["1660-3397"],"issn-type":[{"type":"electronic","value":"1660-3397"}],"subject":[],"published":{"date-parts":[[2025,12,10]]}}}