{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T22:53:51Z","timestamp":1787266431550,"version":"build-2736575974"},"reference-count":138,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Investigaci\u00f3n Valdecilla","award":["NVAL 19\/23"],"award-info":[{"award-number":["NVAL 19\/23"]}]},{"name":"Instituto de Investigaci\u00f3n Valdecilla","award":["CB06\/05\/0037"],"award-info":[{"award-number":["CB06\/05\/0037"]}]},{"name":"Instituto de Investigaci\u00f3n Valdecilla","award":["PID2020-117601RB-I00"],"award-info":[{"award-number":["PID2020-117601RB-I00"]}]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas","award":["NVAL 19\/23"],"award-info":[{"award-number":["NVAL 19\/23"]}]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas","award":["CB06\/05\/0037"],"award-info":[{"award-number":["CB06\/05\/0037"]}]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas","award":["PID2020-117601RB-I00"],"award-info":[{"award-number":["PID2020-117601RB-I00"]}]},{"name":"Agencia Estatal de Investicaci\u00f3n, MICIN","award":["NVAL 19\/23"],"award-info":[{"award-number":["NVAL 19\/23"]}]},{"name":"Agencia Estatal de Investicaci\u00f3n, MICIN","award":["CB06\/05\/0037"],"award-info":[{"award-number":["CB06\/05\/0037"]}]},{"name":"Agencia Estatal de Investicaci\u00f3n, MICIN","award":["PID2020-117601RB-I00"],"award-info":[{"award-number":["PID2020-117601RB-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Oxidative stress (OS) is one of the neuropathological mechanisms responsible for the deficits in cognition and neuronal function in Down syndrome (DS). The Ts65Dn (TS) mouse replicates multiple DS phenotypes including hippocampal-dependent learning and memory deficits and similar brain oxidative status. To better understand the hippocampal oxidative profile in the adult TS mouse, we analyzed cellular OS-associated alterations in hippocampal granule cells (GCs), a neuronal population that plays an important role in memory formation and that is particularly affected in DS. For this purpose, we used biochemical, molecular, immunohistochemical, and electron microscopy techniques. Our results indicate that TS GCs show important OS-associated alterations in the systems essential for neuronal homeostasis: DNA damage response and proteostasis, particularly of the proteasome and lysosomal system. Specifically, TS GCs showed: (i) increased DNA damage, (ii) reorganization of nuclear proteolytic factories accompanied by a decline in proteasome activity and cytoplasmic aggregation of ubiquitinated proteins, (iii) formation of lysosomal-related structures containing lipid droplets of cytotoxic peroxidation products, and (iv) mitochondrial ultrastructural defects. These alterations could be implicated in enhanced cellular senescence, accelerated aging and neurodegeneration, and the early development of Alzheimer\u2019s disease neuropathology present in TS mice and the DS population.<\/jats:p>","DOI":"10.3390\/antiox11122438","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T03:02:37Z","timestamp":1670814157000},"page":"2438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome"],"prefix":"10.3390","volume":"11","author":[{"given":"Alba","family":"Puente-Bedia","sequence":"first","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Farmacolog\u00eda, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda T.","family":"Berciano","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda Molecular, \u201cRed Sobre Enfermedades Neurodegenerativas (CIBERNED)\u201d, Universidad de Cantabria-IDIVAL, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2137-1156","authenticated-orcid":false,"given":"Carmen","family":"Mart\u00ednez-Cu\u00e9","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Farmacolog\u00eda, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3402-1152","authenticated-orcid":false,"given":"Miguel","family":"Lafarga","sequence":"additional","affiliation":[{"name":"Departamento de Anatom\u00eda y Biolog\u00eda Celular, \u201cRed Sobre Enfermedades Neurodegenerativas (CIBERNED)\u201d, Universidad de Cantabria-IDIVAL, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noem\u00ed","family":"Rueda","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda y Farmacolog\u00eda, Facultad de Medicina, Universidad de Cantabria, 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1542\/peds.2009-0745","article-title":"Prevalence of Down syndrome among children and adolescents in 10 regions of the United States","volume":"124","author":"Shin","year":"2009","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-019-0143-7","article-title":"Down syndrome","volume":"6","author":"Antonarakis","year":"2020","journal-title":"Nat. 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