{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T22:54:13Z","timestamp":1787784853734,"version":"build-2784847793"},"reference-count":64,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974540"],"award-info":[{"award-number":["81974540"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274290"],"award-info":[{"award-number":["82274290"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971290"],"award-info":[{"award-number":["81971290"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022ZDLSF02-09"],"award-info":[{"award-number":["2022ZDLSF02-09"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021TD-58"],"award-info":[{"award-number":["2021TD-58"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Research &amp; Development Program of Shaanxi","award":["81974540"],"award-info":[{"award-number":["81974540"]}]},{"name":"Key Research &amp; Development Program of Shaanxi","award":["82274290"],"award-info":[{"award-number":["82274290"]}]},{"name":"Key Research &amp; Development Program of Shaanxi","award":["81971290"],"award-info":[{"award-number":["81971290"]}]},{"name":"Key Research &amp; Development Program of Shaanxi","award":["2022ZDLSF02-09"],"award-info":[{"award-number":["2022ZDLSF02-09"]}]},{"name":"Key Research &amp; Development Program of Shaanxi","award":["2021TD-58"],"award-info":[{"award-number":["2021TD-58"]}]},{"name":"Innovation Capability Support Program of Shaanxi","award":["81974540"],"award-info":[{"award-number":["81974540"]}]},{"name":"Innovation Capability Support Program of Shaanxi","award":["82274290"],"award-info":[{"award-number":["82274290"]}]},{"name":"Innovation Capability Support Program of Shaanxi","award":["81971290"],"award-info":[{"award-number":["81971290"]}]},{"name":"Innovation Capability Support Program of Shaanxi","award":["2022ZDLSF02-09"],"award-info":[{"award-number":["2022ZDLSF02-09"]}]},{"name":"Innovation Capability Support Program of Shaanxi","award":["2021TD-58"],"award-info":[{"award-number":["2021TD-58"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The prevalence of diabetes-associated cognitive dysfunction (DACD) has increased to 13.5%. Dementia, as the most severe DACD, is the second leading cause of death in patients with diabetes mellitus. Hence, the potential mechanisms of DACD for slowing or halting its progression need to be urgently explored. Given that the sigma-1 receptor (Sig-1R), a chaperone protein located in the endoplasmic reticulum (ER)-mitochondrion contact membranes to regulate ER stress (ERS), is associated with cognitive outcomes in neurodegenerative diseases, this study aimed to investigate the role of astrocytic Sig-1R in DACD and its underlying mechanism. Here, we examined the levels of ERS and complement component 3\/3a (C3\/C3a) from primary astrocytes with different concentrations of glucose and treatment. Subsequently, HT22 neurons were cultured in different astrocyte-conditioned medium, and the expression of synaptic proteins was detected. We constructed type 1 diabetes mellitus (T1DM) model to evaluate the astrocytic Sig-1R mechanism on synapse and cognitive function changes. In vitro, high glucose concentration downregulated Sig-1R and aggravated ERS in astrocytes, resulting in synapse deficits. PRE-084, a high-affinity and selective Sig-1R agonist, inhibited astrocytic ERS and complement cascades and restored synaptic damage, while the Sig-1R antagonist displayed the opposite results. Moreover, C3a receptor antagonist (C3aRA) could mimic the effect of PRE-084 and exerted neuroprotective effects. In vivo, PRE-084 substantially reduced ER-mitochondrion contact, activation of ERS, and C3\/C3a secretion in mice with T1DM. Additionally, the synaptic loss and neurobehavioral dysfunction of mice with T1DM were less pronounced in both the PRE-084 and C3aRA treatment groups. These findings demonstrated that Sig-1R activation reduced the astrocytic ER-mitochondrion contact, ERS activation, and complement-mediated synaptic damage in T1DM. This study suggested the mechanisms and potential therapeutic approaches for treating DACD.<\/jats:p>","DOI":"10.3390\/cells12010197","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T02:15:42Z","timestamp":1672798542000},"page":"197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Sigma-1 Receptor as a Protective Factor for Diabetes-Associated Cognitive Dysfunction via Regulating Astrocytic Endoplasmic Reticulum-Mitochondrion Contact and Endoplasmic Reticulum Stress"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1900-1049","authenticated-orcid":false,"given":"Mengyu","family":"Du","sequence":"first","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxuan","family":"He","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5266-6512","authenticated-orcid":false,"given":"Bo","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"},{"name":"Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4110-7894","authenticated-orcid":false,"given":"Lan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-0576","authenticated-orcid":false,"given":"Yansong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3637-2063","authenticated-orcid":false,"given":"Qiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology & Center for Brain Science, The First Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.archger.2015.09.003","article-title":"The prevalence of mild cognitive impairment with type 2 diabetes mellitus among elderly people in China: A cross-sectional study","volume":"62","author":"Gao","year":"2016","journal-title":"Arch. Gerontol. Geriatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S2213-8587(20)30431-9","article-title":"Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: An epidemiological analysis of linked primary care records","volume":"9","author":"Bennett","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.2337\/dc21-0342","article-title":"Incidence of Type 1 Diabetes May Be Underestimated in the Chinese Population: Evidence From 21.7 Million People Between 2007 and 2017","volume":"44","author":"Liu","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1007\/s00125-015-3515-x","article-title":"Risk of dementia in patients hospitalised with type 1 and type 2 diabetes in England, 1998-2011: A retrospective national record linkage cohort study","volume":"58","author":"Smolina","year":"2015","journal-title":"Diabetologia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nrneurol.2017.99","article-title":"ER stress and the unfolded protein response in neurodegeneration","volume":"13","author":"Hetz","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/nrn3689","article-title":"Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases","volume":"15","author":"Hetz","year":"2014","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.cell.2010.02.034","article-title":"Endoplasmic reticulum stress and the inflammatory basis of metabolic disease","volume":"140","author":"Hotamisligil","year":"2010","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5649","DOI":"10.1007\/s12035-021-02524-5","article-title":"Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases","volume":"58","author":"Wu","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhemkov, V., Geva, M., Hayden, M.R., and Bezprozvanny, I. (2021). Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22084082"},{"key":"ref_10","first-page":"97","article-title":"The Role of Sigma-1 Receptor, an Intracellular Chaperone in Neurodegenerative Diseases","volume":"16","author":"Penke","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3389\/fncel.2018.00314","article-title":"Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases","volume":"12","author":"Jia","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_12","first-page":"1461","article-title":"Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders","volume":"18","author":"Tsai","year":"2014","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2174\/156720206776875849","article-title":"Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats","volume":"3","author":"Ajmo","year":"2006","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.nbd.2013.10.010","article-title":"Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation","volume":"62","author":"Peviani","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"570","DOI":"10.2337\/diabetes.54.2.570","article-title":"Complement C3 is a risk factor for the development of diabetes: A population-based cohort study","volume":"54","author":"Hedblad","year":"2005","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4477","DOI":"10.1210\/jc.2017-00948","article-title":"Complement C3 Associates With Incidence of Diabetes, but No Evidence of a Causal Relationship","volume":"102","author":"Muhammad","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S1474-4422(20)30139-3","article-title":"Understanding multifactorial brain changes in type 2 diabetes: A biomarker perspective","volume":"19","author":"Biessels","year":"2020","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.neuron.2018.10.031","article-title":"Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer\u2019s Disease","volume":"100","author":"Litvinchuk","year":"2018","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1523\/JNEUROSCI.2117-15.2016","article-title":"Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer\u2019s Disease","volume":"36","author":"Lian","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/cbf.3496","article-title":"Up-regulation of microRNA-574 attenuates lipopolysaccharide- or cecal ligation and puncture-induced sepsis associated with acute lung injury","volume":"38","author":"Sun","year":"2020","journal-title":"Cell Biochem. Funct."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"857853","DOI":"10.3389\/fphys.2022.857853","article-title":"Acute Endoplasmic Reticulum Stress Induces Inflammation Reaction, Complement System Activation, and Lipid Metabolism Disorder of Piglet Livers: A Proteomic Approach","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1146\/annurev-pathol-031620-113409","article-title":"Complement in Neurologic Disease","volume":"16","author":"Propson","year":"2021","journal-title":"Annu. Rev. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.neuron.2014.11.018","article-title":"NF\u03baB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer\u2019s disease","volume":"85","author":"Lian","year":"2015","journal-title":"Neuron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6087","DOI":"10.1111\/jcmm.13884","article-title":"High glucose-induced complement component 3 up-regulation via RAGE-p38MAPK-NF-\u03baB signalling in astrocytes: In vivo and in vitro studies","volume":"22","author":"Zhao","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13029","DOI":"10.1523\/JNEUROSCI.1698-15.2015","article-title":"Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline","volume":"35","author":"Shi","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/j.celrep.2019.07.060","article-title":"Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy","volume":"28","author":"Wu","year":"2019","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eaaf6295","DOI":"10.1126\/scitranslmed.aaf6295","article-title":"Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP\/PS1 mice","volume":"9","author":"Shi","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1007\/s12035-018-1195-5","article-title":"Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models","volume":"56","author":"Rom","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.15252\/emmm.201606403","article-title":"Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS","volume":"8","author":"Watanabe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.1038\/ncomms4996","article-title":"ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS\/FTD-associated TDP-43","volume":"5","author":"Stoica","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ceca.2007.11.015","article-title":"High- and low-calcium-dependent mechanisms of mitochondrial calcium signalling","volume":"44","author":"Spat","year":"2008","journal-title":"Cell Calcium"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e146323","DOI":"10.1172\/JCI146323","article-title":"Extracellular matrix protein laminin \u03b21 regulates pain sensitivity and anxiodepression-like behaviors in mice","volume":"131","author":"Li","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1038\/nm.3735","article-title":"Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity","volume":"20","author":"Arruda","year":"2014","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1161\/CIRCULATIONAHA.118.033552","article-title":"Hyperglycemia-Driven Inhibition of AMP-Activated Protein Kinase alpha2 Induces Diabetic Cardiomyopathy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes In Vivo","volume":"139","author":"Wu","year":"2019","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s40104-017-0195-z","article-title":"Enriched endoplasmic reticulum-mitochondria interactions result in mitochondrial dysfunction and apoptosis in oocytes from obese mice","volume":"8","author":"Zhao","year":"2017","journal-title":"J. Anim. Sci. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e65192","DOI":"10.7554\/eLife.65192","article-title":"The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains","volume":"10","author":"Zhemkov","year":"2021","journal-title":"eLife"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/978-3-030-12457-1_28","article-title":"At the Crossing of ER Stress and MAMs: A Key Role of Sigma-1 Receptor?","volume":"1131","author":"Delprat","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/978-3-030-12457-1_29","article-title":"ER-Mitochondria Calcium Transfer, Organelle Contacts and Neurodegenerative Diseases","volume":"1131","author":"Vallese","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Liu, Q., Guo, Q., Fang, L.P., Yao, H., Scheller, A., Kirchhoff, F., and Huang, W. (J. Neurochem., 2022). Specific detection and deletion of the sigma-1 receptor widely expressed in neurons and glial cells in vivo, J. Neurochem., early view.","DOI":"10.1101\/2022.06.08.494880"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.phrs.2019.04.026","article-title":"Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer\u2019s disease by positive modulation of \u03c3(1) receptors","volume":"144","author":"Maurice","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4582135","DOI":"10.1155\/2017\/4582135","article-title":"Loss of Sigma-1 Receptor Chaperone Promotes Astrocytosis and Enhances the Nrf2 Antioxidant Defense","volume":"2017","author":"Weng","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1832","DOI":"10.1038\/cddis.2015.194","article-title":"Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons","volume":"6","author":"Hong","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12974-015-0250-7","article-title":"Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression","volume":"12","author":"Zhang","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s12149-007-0094-z","article-title":"Low density of sigma1 receptors in early Alzheimer\u2019s disease","volume":"22","author":"Mishina","year":"2008","journal-title":"Ann. Nucl. Med."},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1600-0404.2005.00432.x","article-title":"Function of sigma1 receptors in Parkinson\u2019s disease","volume":"112","author":"Mishina","year":"2005","journal-title":"Acta Neurol. Scand."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.neurobiolaging.2017.08.007","article-title":"Sigma-1 receptor knockout increases \u03b1-synuclein aggregation and phosphorylation with loss of dopaminergic neurons in substantia nigra","volume":"59","author":"Hong","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2017.11.010","article-title":"Amyloid toxicity is enhanced after pharmacological or genetic invalidation of the \u03c3(1) receptor","volume":"339","author":"Maurice","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1093\/brain\/awu107","article-title":"Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism","volume":"137","author":"Francardo","year":"2014","journal-title":"Brain"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1038\/npp.2013.70","article-title":"Blockade of Tau hyperphosphorylation and A\u03b21\u201342 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and \u03c3\u2081 receptor agonist, in a nontransgenic mouse model of Alzheimer\u2019s disease","volume":"38","author":"Lahmy","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1038\/sj.bjp.0706927","article-title":"The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor","volume":"149","author":"Meunier","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1038\/npp.2008.212","article-title":"Antiamnesic and neuroprotective effects of the aminotetrahydrofuran derivative ANAVEX1-41 against amyloid beta(25-35)-induced toxicity in mice","volume":"34","author":"Villard","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1016\/j.neuropharm.2012.07.035","article-title":"Anti-amnesic effect of neurosteroid PREGS in A\u03b225-35-injected mice through \u03c31 receptor- and \u03b17nAChR-mediated neuroprotection","volume":"63","author":"Yang","year":"2012","journal-title":"Neuropharmacology"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1124\/jpet.113.208330","article-title":"Afobazole activation of \u03c3-1 receptors modulates neuronal responses to amyloid-\u03b225-35","volume":"347","author":"Behensky","year":"2013","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1097\/00001756-200508010-00018","article-title":"Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity","volume":"16","author":"Marrazzo","year":"2005","journal-title":"Neuroreport"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.3233\/JAD-171001","article-title":"Effect of Fluvoxamine on Amyloid-\u03b2 Peptide Generation and Memory","volume":"62","author":"Kim","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.nbd.2018.12.022","article-title":"Pridopidine stabilizes mushroom spines in mouse models of Alzheimer\u2019s disease by acting on the sigma-1 receptor","volume":"124","author":"Ryskamp","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00109-020-01904-z","article-title":"ER stress activates immunosuppressive network: Implications for aging and Alzheimer\u2019s disease","volume":"98","author":"Salminen","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zhao, J., Veeranan-Karmegam, R., Baker, F.C., Mysona, B.A., Bagchi, P., Liu, Y., Smith, S.B., Gonsalvez, G.B., and Bollinger, K.E. (2022). Defining the Ligand-dependent Interactome of the Sigma 1 Receptor. bioRxiv.","DOI":"10.1101\/2022.06.22.497210"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.neuron.2017.08.008","article-title":"Spine Dynamics: Are They All the Same?","volume":"96","author":"Berry","year":"2017","journal-title":"Neuron"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-3-319-50174-1_11","article-title":"Sigma-1 Receptor Agonists and Their Clinical Implications in Neuropsychiatric Disorders","volume":"964","author":"Albayrak","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"15187","DOI":"10.1021\/acs.jmedchem.0c01192","article-title":"Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases","volume":"63","author":"Ye","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/17460441.2021.1838483","article-title":"Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders","volume":"16","author":"Maurice","year":"2021","journal-title":"Expert Opin. Drug Discov."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T17:57:30Z","timestamp":1760119050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,3]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12010197"],"URL":"https:\/\/doi.org\/10.3390\/cells12010197","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,3]]}}}