{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T07:10:16Z","timestamp":1792653016012,"version":"4.5.0"},"reference-count":90,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T00:00:00Z","timestamp":1661299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"NIH","doi-asserted-by":"publisher","award":["GM088213"],"award-info":[{"award-number":["GM088213"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"NIH","doi-asserted-by":"publisher","award":["AG064175"],"award-info":[{"award-number":["AG064175"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer\u2019s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue SEL-12 results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1\/Nrf. Our study reveals that SEL-12\/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1\/Nrf antioxidant activity.<\/jats:p>","DOI":"10.3390\/antiox11091642","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T21:03:51Z","timestamp":1661375031000},"page":"1642","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction"],"prefix":"10.3390","volume":"11","author":[{"given":"Kerry C.","family":"Ryan","sequence":"first","affiliation":[{"name":"Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn T.","family":"Laboy","sequence":"additional","affiliation":[{"name":"Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0773-9073","authenticated-orcid":false,"given":"Kenneth R.","family":"Norman","sequence":"additional","affiliation":[{"name":"Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY 12208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Singh, A., Kukreti, R., Saso, L., and Kukreti, S. (2019). Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules, 24.","DOI":"10.3390\/molecules24081583"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.5607\/en.2015.24.4.325","article-title":"The Role of Oxidative Stress in Neurodegenerative Diseases","volume":"24","author":"Kim","year":"2015","journal-title":"Exp. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13024-020-00376-6","article-title":"Mitochondria dysfunction in the pathogenesis of Alzheimer\u2019s disease: Recent advances","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.bbadis.2013.10.015","article-title":"Oxidative stress and mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"1842","author":"Wang","year":"2014","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s00709-013-0494-y","article-title":"The very many faces of presenilins and the gamma-secretase complex","volume":"250","author":"Smolarkiewicz","year":"2013","journal-title":"Protoplasma"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"ra56","DOI":"10.1126\/scisignal.2003649","article-title":"Regulators of calcium homeostasis identified by inference of kinetic model parameters from live single cells perturbed by siRNA","volume":"6","author":"Bandara","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18195","DOI":"10.1074\/jbc.M000040200","article-title":"Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons","volume":"275","author":"Chan","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.neuron.2008.04.015","article-title":"Mechanism of Ca2+ disruption in Alzheimer\u2019s disease by presenilin regulation of InsP3 receptor channel gating","volume":"58","author":"Cheung","year":"2008","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1073\/pnas.91.2.534","article-title":"Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease","volume":"91","author":"Ito","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1534\/genetics.115.182808","article-title":"A gamma-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans","volume":"201","author":"Sarasija","year":"2015","journal-title":"Genetics"},{"key":"ref_11","first-page":"151","article-title":"PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase-3 by enhancing of ryanodine receptor-mediated calcium release","volume":"20","author":"Lee","year":"2006","journal-title":"FASEB J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1523\/JNEUROSCI.4386-03.2004","article-title":"Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer\u2019s-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability","volume":"24","author":"Stutzmann","year":"2004","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.ceca.2016.06.008","article-title":"When, where and how? Focus on neuronal calcium dysfunctions in Alzheimer\u2019s Disease","volume":"60","author":"Agostini","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e33052","DOI":"10.7554\/eLife.33052","article-title":"Presenilin mutations deregulate mitochondrial Ca(2+) homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans","volume":"7","author":"Sarasija","year":"2018","journal-title":"Elife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/27579","article-title":"Specific interference by ingested dsRNA","volume":"395","author":"Timmons","year":"1998","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature01278","article-title":"Systematic functional analysis of the Caenorhabditis elegans genome using RNAi","volume":"421","author":"Kamath","year":"2003","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"ra22","DOI":"10.1126\/scisignal.2000818","article-title":"Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer\u2019s disease-linked presenilin mutants in human cells and mouse neurons","volume":"3","author":"Cheung","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ceca.2009.12.014","article-title":"The dysregulation of intracellular calcium in Alzheimer disease","volume":"47","author":"Supnet","year":"2010","journal-title":"Cell Calcium"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"344","DOI":"10.2174\/1567205017666200528162046","article-title":"Reversal of Calcium Dysregulation as Potential Approach for Treating Alzheimer\u2019s Disease","volume":"17","author":"Popugaeva","year":"2020","journal-title":"Curr. Alzheimer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e45905","DOI":"10.7554\/eLife.45905","article-title":"Gain-of-function mutations in the UNC-2\/CaV2alpha channel lead to excitation-dominant synaptic transmission in Caenorhabditis elegans","volume":"8","author":"Huang","year":"2019","journal-title":"Elife"},{"key":"ref_21","first-page":"3805","article-title":"Hyperactivation of L-type voltage-gated Ca2+ channels in Caenorhabditis elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the alpha1 subunit","volume":"217","author":"Laine","year":"2014","journal-title":"J. Exp. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Schwarz, J., and Bringmann, H. (2013). Reduced sleep-like quiescence in both hyperactive and hypoactive mutants of the Galphaq Gene egl-30 during lethargus in Caenorhabditis elegans. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075853"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9274","DOI":"10.1073\/pnas.1011711108","article-title":"Genetic analysis of age-dependent defects of the Caenorhabditis elegans touch receptor neurons","volume":"108","author":"Pan","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9279","DOI":"10.1523\/JNEUROSCI.6606-10.2011","article-title":"Spontaneous age-related neurite branching in Caenorhabditis elegans","volume":"31","author":"Tank","year":"2011","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8778","DOI":"10.1523\/JNEUROSCI.1494-11.2012","article-title":"Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system","volume":"32","author":"Toth","year":"2012","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_26","first-page":"e13472","article-title":"Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration","volume":"20","author":"Ryan","year":"2021","journal-title":"Res. Sq."},{"key":"ref_27","first-page":"e3780","article-title":"Simple microfluidic devices for in vivo imaging of C. elegans, Drosophila and zebrafish","volume":"67","author":"Mondal","year":"2012","journal-title":"J. Vis. Exp."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nature21362","article-title":"C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress","volume":"542","author":"Melentijevic","year":"2017","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"13044","DOI":"10.1074\/jbc.M312846200","article-title":"Investigating mitochondrial redox potential with redox-sensitive green fluorescent protein indicators","volume":"279","author":"Hanson","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ceca.2016.05.001","article-title":"Subcellular ROS imaging methods: Relevance for the study of calcium signaling","volume":"60","author":"Booth","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_31","first-page":"51","article-title":"Redox-sensitive green fluorescent protein: Probes for dynamic intracellular redox responses. A review","volume":"476","author":"Cannon","year":"2008","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nmeth.1212","article-title":"Real-time imaging of the intracellular glutathione redox potential","volume":"5","author":"Gutscher","year":"2008","journal-title":"Nat Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1042\/BJ20111770","article-title":"Dynamic measurements of mitochondrial hydrogen peroxide concentration and glutathione redox state in rat pancreatic beta-cells using ratiometric fluorescent proteins: Confounding effects of pH with HyPer but not roGFP1","volume":"441","author":"Roma","year":"2012","journal-title":"Biochem. J."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ghose, P., Park, E.C., Tabakin, A., Salazar-Vasquez, N., and Rongo, C. (2013). Anoxia-reoxygenation regulates mitochondrial dynamics through the hypoxia response pathway, SKN-1\/Nrf, and stomatin-like protein STL-1\/SLP-2. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1004063"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1091\/mbc.e09-10-0874","article-title":"Mitochondrial fragmentation leads to intracellular acidification in Caenorhabditis elegans and mammalian cells","volume":"21","author":"Johnson","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.devcel.2014.08.002","article-title":"elegans epidermal wounding induces a mitochondrial ROS burst that promotes wound repair","volume":"31","author":"Xu","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e13065","DOI":"10.1111\/acel.13065","article-title":"Corrupted ER-mitochondrial calcium homeostasis promotes the collapse of proteostasis","volume":"19","author":"Ashkavand","year":"2020","journal-title":"Aging Cell"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Runkel, E.D., Liu, S., Baumeister, R., and Schulze, E. (2013). Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003346"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1534\/genetics.106.061580","article-title":"Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response","volume":"174","author":"Benedetti","year":"2006","journal-title":"Genetics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4055","DOI":"10.1242\/jcs.01275","article-title":"Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones","volume":"117","author":"Yoneda","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14186","DOI":"10.1074\/jbc.M700827200","article-title":"Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain","volume":"282","author":"Castello","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1074\/jbc.M708597200","article-title":"Complex I is the major site of mitochondrial superoxide production by paraquat","volume":"283","author":"Cocheme","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.2353\/ajpath.2009.090219","article-title":"Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria","volume":"175","author":"Boldogh","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1242\/dev.125.18.3599","article-title":"Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans","volume":"125","author":"Levitan","year":"1998","journal-title":"Development"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1046\/j.1471-4159.1998.70010001.x","article-title":"Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer\u2019s disease","volume":"70","author":"Mattson","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/415092a","article-title":"IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA","volume":"415","author":"Calfon","year":"2002","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41556-018-0205-1","article-title":"mTOR as a central hub of nutrient signalling and cell growth","volume":"21","author":"Kim","year":"2019","journal-title":"Nat. Cell. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"941","DOI":"10.2741\/s310","article-title":"The role of mTOR signaling in Alzheimer disease","volume":"4","author":"Oddo","year":"2012","journal-title":"Front Biosci (Schol. Ed.)"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/nature09706","article-title":"Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB","volume":"470","author":"Mair","year":"2011","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.cmet.2012.04.007","article-title":"TOR signaling and rapamycin influence longevity by regulating SKN-1\/Nrf and DAF-16\/FoxO","volume":"15","author":"Lamming","year":"2012","journal-title":"Cell Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.freeradbiomed.2015.06.008","article-title":"SKN-1\/Nrf, stress responses, and aging in Caenorhabditis elegans","volume":"88","author":"Blackwell","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.molmet.2013.02.002","article-title":"Neuronal ROS signaling rather than AMPK\/sirtuin-mediated energy sensing links dietary restriction to lifespan extension","volume":"2","author":"Schmeisser","year":"2013","journal-title":"Mol. Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1089\/ars.2018.7681","article-title":"Mitochondrial Reactive Oxygen Species Generated at the Complex-II Matrix or Intermembrane Space Microdomain Have Distinct Effects on Redox Signaling and Stress Sensitivity in Caenorhabditis elegans","volume":"31","author":"Trewin","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3563","DOI":"10.1038\/ncomms4563","article-title":"D-Glucosamine supplementation extends life span of nematodes and of ageing mice","volume":"5","author":"Weimer","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Staab, T.A., Evgrafov, O., Knowles, J.A., and Sieburth, D. (2014). Regulation of synaptic nlg-1\/neuroligin abundance by the skn-1\/Nrf stress response pathway protects against oxidative stress. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004100"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1042\/BJ20070521","article-title":"Proteasomal dysfunction activates the transcription factor SKN-1 and produces a selective oxidative-stress response in Caenorhabditis elegans","volume":"409","author":"Kahn","year":"2008","journal-title":"Biochem. J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.cmet.2012.09.007","article-title":"Mitochondrial SKN-1\/Nrf mediates a conserved starvation response","volume":"16","author":"Paek","year":"2012","journal-title":"Cell Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1534\/genetics.119.302504","article-title":"TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging","volume":"213","author":"Blackwell","year":"2019","journal-title":"Genetics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e00429","DOI":"10.7554\/eLife.00429","article-title":"A novel sphingolipid-TORC1 pathway critically promotes postembryonic development in Caenorhabditis elegans","volume":"2","author":"Zhu","year":"2013","journal-title":"Elife"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nature20789","article-title":"Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans","volume":"541","author":"Heintz","year":"2017","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"McCarty, M.F., DiNicolantonio, J.J., and Lerner, A. (2021). A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer\u2019s Pathogenesis-And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22042140"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3233\/JAD-161088","article-title":"Oxidative Stress, Synaptic Dysfunction, and Alzheimer\u2019s Disease","volume":"57","author":"Tonnies","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"e12781","DOI":"10.1111\/cpr.12781","article-title":"The role of astrocytes in oxidative stress of central nervous system: A mixed blessing","volume":"53","author":"Chen","year":"2020","journal-title":"Cell Prolif."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bbamcr.2004.09.006","article-title":"Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture","volume":"1742","author":"Abramov","year":"2004","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Picca, A., Calvani, R., Coelho-Junior, H.J., Landi, F., Bernabei, R., and Marzetti, E. (2020). Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration. Antioxidants, 9.","DOI":"10.3390\/antiox9080647"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4211","DOI":"10.1111\/j.1742-4658.2005.04833.x","article-title":"Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer\u2019s disease brain","volume":"272","author":"Li","year":"2005","journal-title":"FEBS J."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Ma, T., Hoeffer, C.A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M.T., Tampellini, D., Klann, E., Blitzer, R.D., and Gouras, G.K. (2010). Dysregulation of the mTOR pathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer\u2019s disease. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012845"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"8924","DOI":"10.1074\/jbc.M110.180638","article-title":"Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism","volume":"286","author":"Caccamo","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1038\/onc.2016.435","article-title":"Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition","volume":"36","author":"Dermit","year":"2017","journal-title":"Oncogene"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1159\/000441419","article-title":"Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down\u2019s Syndrome","volume":"16","author":"Tramutola","year":"2016","journal-title":"Neurodegener. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.jid.2017.10.007","article-title":"Uncoupling of ER\/Mitochondrial Oxidative Stress in mTORC1 Hyperactivation-Associated Skin Hypopigmentation","volume":"138","author":"Yang","year":"2018","journal-title":"J. Investig. Dermatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e12943","DOI":"10.1111\/acel.12943","article-title":"mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism","volume":"18","author":"Tang","year":"2019","journal-title":"Aging Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1021\/acschemneuro.7b00323","article-title":"Rapamycin Confers Neuroprotection against Colistin-Induced Oxidative Stress, Mitochondria Dysfunction, and Apoptosis through the Activation of Autophagy and mTOR\/Akt\/CREB Signaling Pathways","volume":"9","author":"Dai","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5815","DOI":"10.1007\/s12035-016-0129-3","article-title":"Neuroprotection Through Rapamycin-Induced Activation of Autophagy and PI3K\/Akt1\/mTOR\/CREB Signaling Against Amyloid-beta-Induced Oxidative Stress, Synaptic\/Neurotransmission Dysfunction, and Neurodegeneration in Adult Rats","volume":"54","author":"Singh","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13024-021-00428-5","article-title":"Mammalian\/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration","volume":"16","author":"Querfurth","year":"2021","journal-title":"Mol. Neurodegener."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1101\/gad.1107803","article-title":"SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response","volume":"17","author":"An","year":"2003","journal-title":"Genes Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1111\/acel.12122","article-title":"Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts","volume":"12","author":"Lerner","year":"2013","journal-title":"Aging Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1056\/NEJMoa1210951","article-title":"A phase 3 trial of semagacestat for treatment of Alzheimer\u2019s disease","volume":"369","author":"Doody","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2217\/imt-2018-0119","article-title":"Are antibodies directed against amyloid-beta (Abeta) oligomers the last call for the Abeta hypothesis of Alzheimer\u2019s disease?","volume":"11","author":"Panza","year":"2019","journal-title":"Immunotherapy"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1089\/ars.2018.7506","article-title":"Dysregulation of Intracellular Calcium Signaling in Alzheimer\u2019s Disease","volume":"29","author":"Popugaeva","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cellsig.2015.10.006","article-title":"Beyond gamma-secretase activity: The multifunctional nature of presenilins in cell signalling pathways","volume":"28","author":"Duggan","year":"2016","journal-title":"Cell Signal."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"12045","DOI":"10.1073\/pnas.90.24.12045","article-title":"apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor","volume":"90","author":"Daigle","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1750-1326-7-57","article-title":"Utility of an improved model of amyloid-beta (Abeta(1)(-)(4)(2)) toxicity in Caenorhabditis elegans for drug screening for Alzheimer\u2019s disease","volume":"7","author":"McColl","year":"2012","journal-title":"Mol. Neurodegener."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6537","DOI":"10.1523\/JNEUROSCI.23-16-06537.2003","article-title":"Critical residues of the Caenorhabditis elegans unc-2 voltage-gated calcium channel that affect behavioral and physiological properties","volume":"23","author":"Mathews","year":"2003","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7916","DOI":"10.1073\/pnas.1300677110","article-title":"Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer\u2019s disease and related models","volume":"110","author":"Hedskog","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1038\/emboj.2012.202","article-title":"Upregulated function of mitochondria-associated ER membranes in Alzheimer disease","volume":"31","author":"Tambini","year":"2012","journal-title":"EMBO J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1016\/j.cub.2010.10.057","article-title":"Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity","volume":"20","author":"Lee","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Wu, Z., Senchuk, M.M., Dues, D.J., Johnson, B.K., Cooper, J.F., Lew, L., Machiela, E., Schaar, C.E., DeJonge, H., and Blackwell, T.K. (2018). Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biol., 16.","DOI":"10.1186\/s12915-018-0615-3"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Yang, W., and Hekimi, S. (2010). A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000556"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/9\/1642\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:14:40Z","timestamp":1760141680000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/9\/1642"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,24]]},"references-count":90,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["antiox11091642"],"URL":"https:\/\/doi.org\/10.3390\/antiox11091642","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202207.0152.v1","asserted-by":"object"}]},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,24]]}}}