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Review

The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer’s

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 401-414 | Received 01 Apr 2021, Accepted 03 Jun 2021, Published online: 17 Jun 2021

References

  • Martin WR, Eades CG, Thompson J, et al. The effects of morphine-and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J Pharmacol Exp Ther. 1976;197(3):517–532.
  • Su T-P. Evidence for sigma opioid receptor: binding of [3H] SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther. 1982;223(2):284–290.
  • Hellewell SB, Bowen WD. A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain. Brain Res. 1990;527(2):244–253.
  • Quirion R, Bowen WD, Itzhak Y, et al. A proposal for the classification of sigma binding sites. Trends Pharmacol Sci. 1992;13:85–86.
  • Abbas H, Borde P, Willars GB, et al. Hazards of Using Masking Protocols When Performing Ligand Binding Assays: lessons From the Sigma-1 and Sigma-2 Receptors. Front Pharmacol. 2020;11:309.
  • Hanner M, Moebius FFFF, Flandorfer A, et al. Purification, molecular cloning and expression of the mammalian sigma1-binding site. Proc Nat Acad Sci. 1996;93(15):8072. .
  • Kekuda R, Prasad PDPD, Fei Y-JY-J, et al. Cloning and Functional Expression of the Human Type 1 Sigma Receptor (hSigmaR1)*. Biochem Biophys Res Commun. 1996;229(2):553–558. .
  • Seth P, Leibach FH, Ganapathy V. Cloning and structural analysis of the cDNA and the gene encoding the murine type 1 sigma receptor. Biochem Biophys Res Commun. 1997;241(2):535–540.
  • Schmidt HR, Zheng S, Gurpinar E, et al. Crystal structure of the human σ1 receptor. Nature. 2016;532(7600):527. .
  • Schmidt HR, Betz RM, Dror RO, et al. Structural basis for σ 1 receptor ligand recognition. Nat Struct Mol Biol. 2018;25(10):981.
  • Mishra AK, Mavlyutov T, Singh DR, et al. The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands. Biochem J. 2015;466(2):263–271. .
  • Hong WC. Distinct Regulation of σ1 Receptor Multimerization by Its Agonists and Antagonists in Transfected Cells and Rat Liver Membranes. J Pharmacol Exp Ther. 2020;373(2):290–301.
  • Brimson JM, Brimson S, Chomchoei C, et al. Using Sigma-ligands as part of a multi-receptor approach to target diseases of the brain. In: Expert opinion on therapeutic targets; 2020;24(10):1009-1028.
  • Prince M, Guerchet M, Prina M. The global impact of dementia 2013-2050. Alzheimer’s disease international; 2013.
  • Gauthier S, Cummings J, Ballard C, et al. Management of behavioral problems in Alzheimer’s disease. Int Psychogeriatr. 2010;22(3):346. .
  • Giri M, Zhang M, Lü Y. Genes associated with Alzheimer’s disease: an overview and current status. Clin Interv Aging. 2016;11:665.
  • Jorm AF. Alzheimer’s disease: risk and protection. Med J Aust. 1997;167(8):443–446.
  • Troussière A-C, Charley CM, Salleron J, et al. Treatment of sleep apnoea syndrome decreases cognitive decline in patients with Alzheimer’s disease. J Neurol Neurosurg. 2014;85(12):1405–1408. .
  • Benedict C, Byberg L, Cedernaes J, et al. Self-reported sleep disturbance is associated with Alzheimer’s disease risk in men. Alzheimers Dement. 2015;11(9):1090–1097. .
  • Solfrizzi V, Panza F, Frisardi V, et al. Diet and Alzheimer’s disease risk factors or prevention: the current evidence. Expert Rev Neurother. 2011;11(5):677–708. .
  • Christ MG, Huesmann H, Nagel H, et al. Sigma-1 receptor activation induces autophagy and increases proteostasis capacity in vitro and in vivo. Cells. 8(3): 211. 2019. .
  • Li J-R, Xu H-Z, Nie S, et al. Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subarachnoid hemorrhage in rats. J Neuroinflammation. 2017;14(1):1–14. .
  • Shu X, Sun Y, Sun X, et al. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell Death Dis. 2019;10(8):1–16. .
  • Cho YS, Yen C-N, Shim JS, et al. Antidepressant indatraline induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway. Sci Rep. 2016;6(1):34655. .
  • Klionsky DJ. Autophagy. Curr Biol. 2005;15(8):R282–R283.
  • Tanida I, Ueno T, Kominami E. LC3 and Autophagy. In: Autophagosome and phagosome. Springer; 2008. p. 77–88
  • Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. autophagy. 2021;17(1):1–382.
  • Klionsky DJ. Look people, “Atg” is an abbreviation for “autophagy-related”. That’s it. Autophagy 2012;8(9):1281–1282.
  • Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013;14(12):759–774.
  • Chan EY. Regulation and function of uncoordinated-51 like kinase proteins. Antioxid Redox Signal. 2012;17(5):775–785.
  • Di Bartolomeo S, Corazzari M, Nazio F, et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol. 2010;191(1):155–168. .
  • Komatsu M, Wang QJ, Holstein GR, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Nat Acad Sci. 2007;104(36):14489–14494. .
  • Komatsu M, Waguri S, Chiba T, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441(7095):880–884. .
  • Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885–889. .
  • Nixon RA, Wegiel J, Kumar A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol. 2005;64(2):113–122. .
  • Boland B, Kumar A, Lee S, et al. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci. 2008;28(27):6926–6937. .
  • Lee J-H, Yu WH, Kumar A, et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141(7):1146–1158. .
  • Xie Y, Kang R, Tang D. Role of the Beclin 1 Network in the Cross-Regulation between Autophagy and Apoptosis. In: Autophagy: cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging. Academic PressElsevier; 2016. p. 75–88.
  • Pickford F, Masliah E, Britschgi M, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J Clin Invest. 2008;118(6):2190–2199. .
  • Small SA, Kent K, Pierce A, et al. Model‐guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol. 2005;58(6):909–919. .
  • Berger Z, Davies JE, Luo S, et al. Deleterious and protective properties of an aggregate-prone protein with a polyalanine expansion. Hum Mol Genet. 2006;15(3):453–465. .
  • Krüger U, Wang Y, Kumar S, et al. Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging. 2012;33(10):2291–2305. .
  • Luna-Munoz J, Chavez-Macias L, Garcia-Sierra F, et al. Earliest Stages of Tau Conformational Changes are Related to the Appearance of a Sequence of Specific Phospho-Dependent Tau Epitopes in Alzheimer’s Disease 1. J Alzheimers Dis. 2007;12(4):365–375. .
  • Frake RA, Ricketts T, Menzies FM, et al. Autophagy and neurodegeneration. J Clin Invest. 2015;125(1):65–74. .
  • Rahman MA, Rahman MS, Rahman MH, et al. Promising modulatory effects of autophagy on APP processing as a potential treatment for Alzheimer’s disease. 2020.
  • Murphy MP. How mitochondria produce reactive oxygen species. Biochem J. 2009;417(1):1–13.
  • Salminen A, Kaarniranta K, Kauppinen A, et al. Impaired autophagy and APP processing in Alzheimer’s disease: the potential role of Beclin 1 interactome. Prog Neurobiol. 2013;106:33–54.
  • Li L, Zhang X, Le W. Autophagy dysfunction in Alzheimer’s disease. Neurodegen Dis. 2010;7(4):265–271.
  • Son SM, Song H, Byun J, et al. Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions. Autophagy. 2012;8(12):1842–1844. .
  • Joshi G, Gan KA, Johnson DA, et al. Increased Alzheimer’s disease–like pathology in the APP/PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging. 2015;36(2):664–679. .
  • Zare-Shahabadi A, Masliah E, Johnson GV, et al. Autophagy in Alzheimer’s disease. Rev Neurosci. 2015;26(4):385–395. .
  • Funderburk SF, Marcellino BK, Yue Z. Cell “self‐eating”(autophagy) mechanism in Alzheimer’s disease. Mt Sinai J Med. 2010;77(1):59–68.
  • Yang D-S, Kumar A, Stavrides P, et al. Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer’s disease. Am J Pathol. 2008;173(3):665–681. .
  • Hamasaki M, Furuta N, Matsuda A, et al. Autophagosomes form at ER–mitochondria contact sites. Nature. 2013;495(7441):389–393. .
  • Yang H, Shen H, Li J, et al. Sigma-1 receptor ablation impairs autophagosome clearance. Autophagy. 2019;14.
  • Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol. 2010;12(9):823–830.
  • Langa F, Codony X, Tovar V, et al. Generation and phenotypic analysis of sigma receptor type I (σ1) knockout mice. Eur J Neurosci. 2003;18(8):2188–2196. .
  • Sabino V, Cottone P, Parylak SL, et al. Sigma-1 receptor knockout mice display a depressive-like phenotype. Behav Brain Res. 2009;198(2):472–476. .
  • Korpis K, Weber F, Brune S, et al. Involvement of apoptosis and autophagy in the death of RPMI 8226 multiple myeloma cells by two enantiomeric sigma receptor ligands. Bioorg Med Chem. 2014;22(1):221–233. .
  • Schrock JM, Spino CM, Longen CG, et al. Sequential Cytoprotective Responses to Sigma1 Ligand–Induced Endoplasmic Reticulum Stress. Mol Pharmacol. 2013;84(5):751–762. .
  • Hindmarch I, Hashimoto K. Cognition and depression: the effects of fluvoxamine, a sigma‐1 receptor agonist, reconsidered. Hum Psychopharmacol Clin Exp. 2010;25(3):193–200.
  • Robson MJ, Elliott M, Seminerio MJ, et al. Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. Eur Neuropsychopharmacol. 2012;22(4):308–317. .
  • Tatsumi M, Groshan K, Blakely RD, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340(2–3):249–258. .
  • Jeon S-H, Kim SH, Kim Y, et al. The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells. Biochem Biophys Res Commun. 2011;413(2):311–317. .
  • Ordoñez R, Fernández A, Prieto‐Domínguez N, et al. Ceramide metabolism regulates autophagy and apoptotic cell death induced by melatonin in liver cancer cells. J Pineal Res. 2015;59(2):178–189. .
  • Rossi M, Munarriz ER, Bartesaghi S, et al. Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux. J Cell Sci. 2009;122(18):3330–3339. .
  • Su T-P, Hayashi T, Maurice T, et al. The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci. 2010;31(12):557–566. .
  • Bolshakova AV, Kukanova EO, Gainullina AN, et al. Sigma-1 receptor as a potential pharmacological target for the treatment of neuropathology. St Petersburg Polytech Univ J. 2016;2(1):31–40. .
  • Wang X, Li Y, Deuther-Conrad W, et al. Synthesis and biological evaluation of 18F labeled fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives for sigma-1 receptor imaging. Bioorg Med Chem. 2013;21(1):215–222. .
  • Toyohara J, Sakata M, Ishiwata K. Re-evaluation of in vivo selectivity of [11C] SA4503 to σ1 receptors in the brain: contributions of emopamil binding protein. Nucl Med Biol. 2012;39(7):1049–1052.
  • Wang I-F, Tsai K-J, Shen C-KJ. Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies. Autophagy. 2013;9(2):239–240.
  • Kaverina NV, Kadagidze ZG, Borovjagin AV, et al. Tamoxifen overrides autophagy inhibition in Beclin-1-deficient glioma cells and their resistance to adenovirus-mediated oncolysis via upregulation of PUMA and BAX. Oncogene. 2018;37(46):6069–6082. .
  • Cho KS, Yoon YH, Choi JA, et al. Induction of autophagy and cell death by tamoxifen in cultured retinal pigment epithelial and photoreceptor cells. Invest Ophthalmol Vis Sci. 2012;53(9):5344–5353. .
  • Torres‐López L, Maycotte P, Liñán‐Rico A, et al. Tamoxifen induces toxicity, causes autophagy, and partially reverses dexamethasone resistance in Jurkat T cells. J Leukoc Biol. 2019;105(5):983–998. .
  • Graham CD, Kaza N, Klocke BJ, et al. Tamoxifen induces cytotoxic autophagy in glioblastoma. J Neuropathol Exp Neurol. 2016;75(10):946–954. .
  • O’Neill K, Chen S, Brinton RD. Impact of the selective estrogen receptor modulator, tamoxifen, on neuronal outgrowth and survival following toxic insults associated with aging and Alzheimer’s disease. Exp Neurol. 2004;188(2):268–278.
  • Wang X, Wang W, Li L, et al. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis. 2014;1842(8):1240–1247. .
  • Ghosh Ghosh I, Sankhe R, Mudgal J, et al. Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders. Neuropeptides. 2020:102083
  • Rahman MA, Rhim H. Therapeutic implication of autophagy in neurodegenerative diseases. BMB Rep. 2017;50(7):345.
  • Cuervo AM, Bergamini E, Brunk UT, et al. Autophagy and aging: the importance of maintaining” clean” cells. Autophagy. 2005;1(3):131–140. .
  • Hara Y, McKeehan N, Fillit HM. Translating the biology of aging into novel therapeutics for Alzheimer disease. Neurology. 2019;92(2):84–93.
  • Gruendler R, Hippe B, Sendula Jengic V, et al. Nutraceutical Approaches of Autophagy and Neuroinflammation in Alzheimer’s Disease: a Systematic Review. Molecules. 2020;25(24):6018. .
  • Rahman MA, Bishayee K, Habib K, et al. 18α-Glycyrrhetinic acid lethality for neuroblastoma cells via de-regulating the Beclin-1/Bcl-2 complex and inducing apoptosis. Biochem Pharmacol. 2016;117:97–112.
  • Rahman MA, Bishayee K, Sadra A, et al. Oxyresveratrol activates parallel apoptotic and autophagic cell death pathways in neuroblastoma cells. Biochim Biophys Acta. 2017;1861(2):23–36. .
  • Mputhia Z, Hone E, Tripathi T, et al. Autophagy modulation as a treatment of amyloid diseases. Molecules. 2019;24(18):3372. .
  • Congdon EE, Wu JW, Myeku N, et al. Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo. Autophagy. 2012;8(4):609–622. .
  • Di Meco A, Li J-G, Blass BE, et al. 12/15-Lipoxygenase inhibition reverses cognitive impairment, brain amyloidosis, and tau pathology by stimulating autophagy in aged triple transgenic mice. Biol Psychiatry. 2017;81(2):92–100. .
  • Nixon RA. Autophagy, amyloidogenesis and Alzheimer's disease. J Cell Sci. 2007;120(23):4081–4091.
  • Tian Y, Bustos V, Flajolet M, et al. A small‐molecule enhancer of autophagy decreases levels of Aβ and APP‐CTF via Atg5‐dependent autophagy pathway. FASEB J. 2011;25(6):1934–1942. .
  • Li C, Guo X-D, Lei M, et al. Thamnolia vermicularis extract improves learning ability in APP/PS1 transgenic mice by ameliorating both Aβ and Tau pathologies. Acta Pharmacol Sin. 2017;38(1):9–28. .
  • Chow VW, Mattson MP, Wong PC, et al. An overview of APP processing enzymes and products. Neuromolecular Med. 2010;12(1):1–12. .
  • Bekris L, Galloway N, Millard S, et al. Amyloid precursor protein (APP) processing genes and cerebrospinal fluid APP cleavage product levels in Alzheimer’s disease. Neurobiol Aging. 2011;32(3):556.e13–556. e23. .
  • Li F, Chung T, Vierstra RD. AUTOPHAGY-RELATED11 plays a critical role in general autophagy-and senescence-induced mitophagy in Arabidopsis. Plant Cell. 2014;26(2):788–807.
  • Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer’s disease Aβ peptide. Bioessays. 2014;36(6):570–578.
  • O’Keefe L, Denton D. Using Drosophila models of amyloid toxicity to study autophagy in the pathogenesis of Alzheimer’s disease. Biomed Res Int. 2018;2018:2018.
  • Wen J, Fang F, Guo S-H, et al. Amyloid β-derived diffusible ligands (ADDLs) induce abnormal autophagy associated with Aβ aggregation degree. J Mol Neurosci. 2018;64(2):162–174. .
  • Liu J, Li L. Targeting Autophagy for the Treatment of Alzheimer’s Disease: challenges and Opportunities. Front Mol Neurosci. 2019;12:203.
  • Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41(10):1088–1093. .
  • Kok E, Haikonen S, Luoto T, et al. Apolipoprotein E–dependent accumulation of Alzheimer disease–related lesions begins in middle age. Ann Neurol. 2009;65(6):650–657. .
  • Parcon PA, Balasubramaniam M, Ayyadevara S, et al. Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs. Alzheimers Dement. 2018;14(2):230–242. .
  • Gundlach AL, Largent BL, Snyder SH. Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+) 3H-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine. J Neurosci. 1986;6(6):1757–1770.
  • Sánchez-Fernández C, Entrena JM, Baeyens JM, et al. Sigma-1 receptor antagonists: a new class of neuromodulatory analgesics. In: Sigma Receptors: their Role in Disease and as Therapeutic Targets: springer. 2017. p. 109–132.
  • Su T-P, Hayashi T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Curr Med Chem. 2003;10(20):2073–2080.
  • De B, Nadal X, Portillo-salido E, et al. Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury. Pain. 2009;145(3):294–303. .
  • Nieto FR, Cendán CM, Sánchez-Fernández C, et al. Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain. 2012;13(11):1107–1121. .
  • Zamanillo D, Romero L, Merlos M, et al. Sigma 1 receptor: a new therapeutic target for pain. Eur J Pharmacol. 2013;716(1–3):78–93. .
  • Brimson JM, Safrany ST, Qassam H, et al. Dipentylammonium Binds to the Sigma-1 Receptor and Protects Against Glutamate Toxicity, Attenuates Dopamine Toxicity and Potentiates Neurite Outgrowth in Various Cultured Cell Lines. Neurotox Res. 2018;34(2):263–272. .
  • Villard V, Espallergues J, Keller E, et al. Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol. 2011;25(8):1101–1117. .
  • Frecska E, Szabo A, Winkelman MJ, et al. A possibly sigma-1 receptor mediated role of dimethyltryptamine in tissue protection, regeneration, and immunity. J Neural Transm. 2013;120(9):1295–1303. .
  • Pal A, Fontanilla D, Gopalakrishnan A, et al. The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol. 2012;682(1–3):12–20. .
  • Hayashi T, Tsai S-YS-Y, Mori T, et al. Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders. Expert Opinion Ther Targets. 2011;15(5):557–577. .
  • Ishima T, Fujita Y, Hashimoto K. Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol. 2014;727:167–173.
  • Nishimura T, Ishima T, Iyo M, et al. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways. PLoS One. 2008;3(7):e2558–e2558. .
  • Ishima T, Hashimoto K. Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by ifenprodil: the role of sigma-1 and IP3 receptors. PloS One. 2012;7(5):e37989–e37989.
  • Kawamura K, Kimura Y, Tsukada H, et al. An increase of sigma1 receptors in the aged monkey brain. Neurobiol Aging. 24(5): 745–752. 2003. .
  • Wallace DR, Mactutus CF, Booze RM. Sigma binding sites identified by [3H] DTG are elevated in aged Fischer‐344× Brown Norway (F1) rats. Synapse. 2000;35(4):311–313. .
  • Horsager J, Fedorova TD, Berge NV, et al. Cardiac 11C-Donepezil Binding Increases With Age in Healthy Humans: potentially Signifying Sigma-1 Receptor Upregulation. J Cardiovasc Pharmacol Ther. 24(4): 365–370. 2019. .
  • Norbury R, Travis MJ, Erlandsson K, et al. In vivo imaging of muscarinic receptors in the aging female brain with (R, R)[123I]-I-QNB and single photon emission tomography. Exp Gerontol. 2005;40(3):137–145. .
  • Inoue M, Suhara T, Sudo Y, et al. Age-related reduction of extrastriatal dopamine D2 receptor measured by PET. Life Sci. 2001;69(9):1079–1084. .
  • Sheline YI, Mintun MA, Moerlein SM, et al. Greater loss of 5-HT2A receptors in midlife than in late life. Am J Psychiatry. 2002;159(3):430–435. .
  • Mishina M, Ohyama M, Ishii K, et al. Low density of sigma 1 receptors in early Alzheimer’s disease. Ann Nucl Med. 22(3): 151. 2008. .
  • Cataldo AM, Barnett JL, Berman SA, et al. Gene expression and cellular content of cathepsin D in Alzheimer’s disease brain: evidence for early up-regulation of the endosomal-lysosomal system. Neuron. 1995;14(3):671–680. .
  • Barnett A, Brewer GJ. Autophagy in aging and Alzheimer’s disease: pathologic or protective? J Alzheimers Dis. 2011;25(3):385–394.
  • Holmes C, Boche D, Wilkinson D, et al. Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372(9634):216–223. .
  • Lacor PN, Buniel MC, Furlow PW, et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 2007;27(4):796–807. .
  • Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature. 1995;373(6514):523–527. .
  • Pannuzzo M. On the physiological/pathological link between Aβ peptide, cholesterol, calcium ions and membrane deformation: a molecular dynamics study. Biochimi Biophys Acta (BBA) Biomembr. 2016;1858(6):1380–1389.
  • Hayashi T, Su T-P. Sigma-1 Receptor Chaperones at the ER- Mitochondrion Interface Regulate Ca 2 + Signaling and Cell Survival. Cell. 2007;131(3):596–610.
  • Wu Z, Bowen WD. Role of Sigma-1 Receptor C-terminal Segment in Inositol 1, 4, 5-Trisphosphate Receptor Activation. J Biol Chem. 2008;283(42):28198–28215.
  • Csordás G, Renken C, Várnai P, et al. Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol. 2006;174(7):915–921.
  • Hayashi T. Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs. J Pharmacol Sci. 2015;127(1):2–5.
  • Antonini V, Marrazzo A, Kleiner G, et al. Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion. J Alzheimers Dis. 2011;24(3):569–586. .
  • Maurice T. Protection by sigma-1 receptor agonists is synergic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. Behav Brain Res. 2016;296:270–278.
  • Hall H, Iulita MF, Gubert P, et al. AF710B, an M1/sigma-1 receptor agonist with long-lasting disease-modifying properties in a transgenic rat model of Alzheimer’s disease. Alzheimer’s Dementia. 2018;14(6):811–823. .
  • Kametani F, Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front Neurosci. 2018;12:25.
  • Mohandas E, Rajmohan V, Raghunath B. Neurobiology of Alzheimer’s disease. Indian J Psychiatry. 2009;51(1):55.
  • Cleveland DW, Hwo S-Y, Kirschner MW. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol. 1977;116(2):207–225.
  • Tsai S-YA, Pokrass MJ, Klauer NR, et al. Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid. Proc Nat Acad Sci. 2015;112(21):6742–6747. .
  • Caccamo A, Oddo S, Billings LM, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. 2006;49(5):671–682. .
  • Hayashi T, Fujimoto M. Detergent-resistant microdomains determine the localization of σ-1 receptors to the endoplasmic reticulum-mitochondria junction. Mol Pharmacol. 2010;77(4):517–528.
  • Palmer CP, Mahen R, Schnell E, et al. Sigma-1 receptors bind cholesterol and remodel lipid rafts in breast cancer cell lines. Cancer Res. 2007;67(23):11166–11175. .
  • Hayashi T, Su TP. The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: implication for drug abuse. Life Sci. 2005;77(14):1612–1624.
  • Hayashi T, Su T-P. σ-1 Receptors (σ1 binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther. 2003;306(2):718–725.
  • Pabba M, Wong AY, Ahlskog N, et al. NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus. J Neurosci. 2014;34(34):11325–11338. .
  • Hayashi T, Su T-P. Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation. Proc Nat Acad Sci. 2004;101(41):14949–14954.
  • Ruscher K, Shamloo M, Rickhag M, et al. The sigma-1 receptor enhances brain plasticity and functional recovery after experimental stroke. Brain. 2011;134(3):732–746. .
  • Takebayashi M, Hayashi T, Su TP. σ‐1 Receptors potentiate epidermal growth factor signaling towards neuritogenesis in PC12 cells: potential relation to lipid raft reconstitution. Synapse. 2004;53(2):90–103.
  • Lahmy V, Meunier J, Malmström S, et al. Blockade of Tau hyperphosphorylation and Aβ 1–42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ 1 receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2013;38(9):1706. .
  • Nguyen PTH, Kimura T, Ho SA, et al. Ameliorative effects of a neuroprotective agent, T‐817MA, on place learning deficits induced by continuous infusion of amyloid‐β peptide (1–40) in rats. Hippocampus. 2007;17(6):443–455. .
  • Molander‐Melin M, Blennow K, Bogdanovic N, et al. Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent‐resistant membrane domains. J Neurochem. 2005;92(1):171–182. .
  • Pernber Z, Blennow K, Bogdanovic N, et al. Altered distribution of the gangliosides GM1 and GM2 in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2012;33(2–3):174–188. .
  • Jaeger PA, Pickford F, Sun C-H, et al. Regulation of amyloid precursor protein processing by the Beclin 1 complex. PloS One. 2010;5(6):e11102. .
  • Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303.
  • Huang Y, Zheng L, Halliday G, et al. Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer’s disease. Curr Alzheimer Res. 2011;8(7):765–770. .
  • Hayashi T, Su TP. The sigma receptor: evolution of the concept in neuropsychopharmacology. Curr Neuropharmacol. 2005;3(4):267–280.
  • Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: a 24-week, randomized, double-blind study. Clin Ther. 2010 Jul;32(7):1234–1251. .
  • Jia J, Wei C, Jia L, et al. Efficacy and Safety of Donepezil in Chinese Patients with Severe Alzheimer’s Disease: a Randomized Controlled Trial. J Alzheimers Dis. 2017;56(4):1495–1504. .
  • Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. The Donepezil Study Group. Dementia 1996 Nov-Dec;7(6):293–303. .
  • Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc. 2001 Dec;49(12):1590–1599. .
  • Swedish Council on Health Technology A. SBU Systematic Reviews. Dementia – caring, Ethics, Ethnical and Economical Aspects: a Systematic Review. Stockholm: Swedish Council on Health Technology Assessment (SBU). Copyright © 2008 by the Swedish Council on Health Technology Assessment; 2008.
  • Ramakrishnan NK, Visser AK, Schepers M, et al. Dose-dependent sigma-1 receptor occupancy by donepezil in rat brain can be assessed with 11 C-SA4503 and microPET. Psychopharmacology (Berl). 2014;231(20):3997–4006. .
  • Ishima T, Nishimura T, Iyo M, et al. Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by donepezil: role of sigma-1 receptors and IP3 receptors. Prog Neuro Psychopharmacol Biol Psychiatry. 2008;32(7):1656–1659. .
  • Solntseva E, Kapai N, Popova O, et al. The involvement of sigma1 receptors in donepezil-induced rescue of hippocampal LTP impaired by beta-amyloid peptide. Brain Res Bull. 2014;106:56–61.
  • Inagaki S, Funato M, Nakamura S, et al. Donepezil, an anti-Alzheimer’s disease drug has the neuroprotective effect on RGCs derived from familial glaucoma patients’ iPS cells. Invest Ophthalmol Vis Sci. 2019;60(9):626.
  • Kim E, Park M, Jeong J, et al. Cholinesterase inhibitor donepezil increases mitochondrial biogenesis through AMP-activated protein kinase in the hippocampus. Neuropsychobiology. 2016;73(2):81–91. .
  • Lahmy V, Long R, Morin D, et al. Mitochondrial protection by the mixed muscarinic/σ1 ligand ANAVEX2-73, a tetrahydrofuran derivative, in Aβ25–35 peptide-injected mice, a nontransgenic Alzheimer’s disease model. Front Cell Neurosci. 2015;8:463.
  • Macfarlane S, Cecchi M, Moore D, et al. New Exploratory Alzheimer’s Drug ANAVEX 2-73 Changes in Electrophysiological Markers in Alzheimer’s Disease-First Patient Data from an ongoing Phase 2a Study in mild-to-moderate Alzheimer’s Patients. Clin Neuropharmacol. 2002;25(4):207–215. .
  • Garnock-Jones KP. Dextromethorphan/Quinidine. CNS Drugs. 2011;25(5):435–445.
  • Chou Y-C, Liao J-F, Chang W-Y, et al. Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan. Brain Res. 1999;821(2):516–519. .
  • Nguyen L, Robson MJ, Healy JR, et al. Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PloS One. 2014;9(2):e89985. .
  • Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer's disease dementia: a randomized clinical trial. Jama. 2015;314(12):1242–1254. .
  • Fukushima T, Koide M, Ago Y, et al. T-817MA, a novel neurotrophic agent, improves sodium nitroprusside-induced mitochondrial dysfunction in cortical neurons. Neurochem Int. 2006;48(2):124–130. .
  • Kimura T, Hong Nguyen PT, Ho SA, et al. T‐817MA, a neurotrophic agent, ameliorates the deficits in adult neurogenesis and spatial memory in rats infused icv with amyloid‐β peptide. Br J Pharmacol. 2009;157(3):451–463. .
  • Fukushima T, Nakamura A, Iwakami N, et al. T-817MA, a neuroprotective agent, attenuates the motor and cognitive impairments associated with neuronal degeneration in P301L tau transgenic mice. Biochem Biophys Res Commun. 2011;407(4):730–734. .
  • Schneider LS, Thomas RG, Hendrix S, et al. Safety and efficacy of edonerpic maleate for patients with mild to moderate Alzheimer's disease: a phase 2 randomized clinical trial. JAMA Neurol. 2019;76(11):1330–1339. .
  • Pandey D, Banerjee S, Basu M, et al. Memory enhancement by Tamoxifen on amyloidosis mouse model. Horm Behav. 2016;79:70–73.
  • Karimi S, Hejazian SH, Alikhani V, et al. The effects of tamoxifen on spatial and nonspatial learning and memory impairments induced by scopolamine and the brain tissues oxidative damage in ovariectomized rats. Adv Biomed Res. 2015;4:4.
  • Zabihi H, Hosseini M, Pourganji M, et al. The effects of tamoxifen on learning, memory and brain tissues oxidative damage in ovariectomized and naive female rats. Adv Biomed Res. 2014;3:3.
  • Maurice T. Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders. In: Expert Opinion on Drug Discovery. 2020. p. 1–17.
  • Breuer B, Anderson R. The relationship of tamoxifen with dementia, depression, and dependence in activities of daily living in elderly nursing home residents. Women Health. 2000;31(1):71–85.
  • Sun L-M, Chen H-J, Liang J-A, et al. Long-term use of tamoxifen reduces the risk of dementia: a nationwide population-based cohort study. QJM. 2015;109(2):103–109. .
  • Bromley SE, Matthews A, Smeeth L, et al. Risk of dementia among postmenopausal breast cancer survivors treated with aromatase inhibitors versus tamoxifen: a cohort study using primary care data from the UK. J Cancer Survivorship. 2019;13(4):632–640. .
  • Nguyen L, Lucke-Wold BP, Mookerjee SA, et al. Role of sigma-1 receptors in neurodegenerative diseases. J Pharmacol Sci. 2015;127(1):17–29. .
  • Moriguchi S, Shinoda Y, Yamamoto Y, et al. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice. PloS One. 2013;8(4):e60863–e60863. .
  • Rosen DA, Seki SM, Fernández-Castañeda A, et al. Modulation of the sigma-1 receptor–IRE1 pathway is beneficial in preclinical models of inflammation and sepsis. Sci Transl Med. 2019;11(478):eaau5266. .
  • Maurice T, Volle J-N, Strehaiano M, et al. Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer’s disease by positive modulation of σ1 receptors. Pharmacol Res. 2019;144:315–330.
  • Zvejniece L, Vavers E, Svalbe B, et al. The cognition‐enhancing activity of E1R, a novel positive allosteric modulator of sigma‐1 receptors. Br J Pharmacol. 2014;171(3):761–771. .
  • Guo L, Chen Y, Zhao R, et al. Allosteric modulation of sigma‐1 receptors elicits anti‐seizure activities. Br J Pharmacol. 2015;172(16):4052–4065. .
  • Rubinsztein David C, Mariño G, Kroemer G. Autophagy and Aging. Cell. 2011;146(5):682–695.

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