Astrocytes in depression and Alzheimer’s disease

Abstract

Astrocytes are an abundant subgroup of cells in the central nervous system (CNS) that play a critical role in controlling neuronal circuits involved in emotion, learning, and memory. In clinical cases, multiple chronic brain diseases may cause psychosocial and cognitive impairment, such as depression and Alzheimer’s disease (AD). For years, complex pathological conditions driven by depression and AD have been widely perceived to contribute to a high risk of disability, resulting in gradual loss of self-care ability, lower life qualities, and vast burden on human society. Interestingly, correlational research on depression and AD has shown that depression might be a prodrome of progressive degenerative neurological disease. As a kind of multifunctional glial cell in the CNS, astrocytes maintain physiological function via supporting neuronal cells, modulating pathologic niche, and regulating energy metabolism. Mounting evidence has shown that astrocytic dysfunction is involved in the progression of depression and AD. We herein review the current findings on the roles and mechanisms of astrocytes in the development of depression and AD, with an implication of potential therapeutic avenue for these diseases by targeting astrocytes.

Keywords

astrocytes / depression / Alzheimer’s disease / roles / mechanisms

References

[1] Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999; 22(5): 208–215

[2] Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 2005; 6(8): 626–640

[3] Blanco-Suárez E, Caldwell AL, Allen NJ. Role of astrocyte-synapse interactions in CNS disorders. J Physiol 2017; 595(6): 1903–1916

[4] Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 2015; 18(7): 942–952

[5] Stogsdill JA, Ramirez J, Liu D, Kim YH, Baldwin KT, Enustun E, Ejikeme T, Ji RR, Eroglu C. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 2017; 551(7679): 192–197

[6] Khakh BS. Astrocyte-neuron interactions in the striatum: insights on identity, form, and function. Trends Neurosci 2019; 42(9): 617–630

[7] Campisi M, Shin Y, Osaki T, Hajal C, Chiono V, Kamm RD. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials 2018; 180: 117–129

[8] Liddelow SA, Marsh SE, Stevens B. Microglia and astrocytes in disease: dynamic duo or partners in crime? Trends Immunol 2020; 41(9): 820–835

[9] Alexopoulos GS. Depression in the elderly. Lancet 2005; 365(9475): 1961–1970

[10] Cui R. Editorial: a systematic review of depression. Curr Neuropharmacol 2015; 13(4): 480

[11] Gaynes B. Assessing the risk factors for difficult-to-treat depression and treatment-resistant depression. J Clin Psychiatry 2016; 77(Suppl 1): 4–8

[12] Wang J, Wu X, Lai W, Long E, Zhang X, Li W, Zhu Y, Chen C, Zhong X, Liu Z, Wang D, Lin H. Prevalence of depression and depressive symptoms among outpatients: a systematic review and meta-analysis. BMJ Open 2017; 7(8): e017173

[13] World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organization, 2017

[14] Malhi GS, Mann JJ. Depression. Lancet 2018; 392(10161): 2299–2312

[15] Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: beyond monoamine hypothesis. Psychiatry Clin Neurosci 2018; 72(1): 3–12

[16] David DJ, Gardier AM. The pharmacological basis of the serotonin system: application to antidepressant response. Encephale 2016; 42(3): 255–263 (in French)

[17] Oxenkrug G. Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Curr Drug Targets 2013; 14(5): 514–521

[18] Takahashi S. Reduction of blood platelet serotonin levels in manic and depressed patients. Folia Psychiatr Neurol Jpn 1976; 30(4): 475–486

[19] Rojas PS, Fiedler JL. What do we really know about 5-HT_1A receptor signaling in neuronal cells? Front Cell Neurosci 2016; 10: 272

[20] Teixeira CM, Rosen ZB, Suri D, Sun Q, Hersh M, Sargin D, Dincheva I, Morgan AA, Spivack S, Krok AC, Hirschfeld-Stoler T, Lambe EK, Siegelbaum SA, Ansorge MS. Hippocampal 5-HT input regulates memory formation and Schaffer collateral excitation. Neuron 2018; 98(5): 992–1004.e4

[21] Naharci MI, Buyukturan O, Cintosun U, Doruk H, Tasci I. Functional status of older adults with dementia at the end of life: is there still anything to do? Indian J Palliat Care 2019; 25(2): 197–202

[22] Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement 2016; 12(4): 459–509

[23] Jia J, Wei C, Chen S, Li F, Tang Y, Qin W, Zhao L, Jin H, Xu H, Wang F, Zhou A, Zuo X, Wu L, Han Y, Han Y, Huang L, Wang Q, Li D, Chu C, Shi L, Gong M, Du Y, Zhang J, Zhang J, Zhou C, Lv J, Lv Y, Xie H, Ji Y, Li F, Yu E, Luo B, Wang Y, Yang S, Qu Q, Guo Q, Liang F, Zhang J, Tan L, Shen L, Zhang K, Zhang J, Peng D, Tang M, Lv P, Fang B, Chu L, Jia L, Gauthier S. The cost of Alzheimer’s disease in China and re-estimation of costs worldwide. Alzheimers Dement 2018; 14(4): 483–491

[24] Pan RY, Ma J, Kong XX, Wang XF, Li SS, Qi XL, Yan YH, Cheng J, Liu Q, Jin W, Tan CH, Yuan Z. Sodium rutin ameliorates Alzheimer’s disease-like pathology by enhancing microglial amyloid-β clearance. Sci Adv 2019; 5(2): eaau6328

[25] Realdon O, Rossetto F, Nalin M, Baroni I, Cabinio M, Fioravanti R, Saibene FL, Alberoni M, Mantovani F, Romano M, Nemni R, Baglio F. Technology-enhanced multi-domain at home continuum of care program with respect to usual care for people with cognitive impairment: the Ability-TelerehABILITation study protocol for a randomized controlled trial. BMC Psychiatry 2016; 16(1): 425

[26] Barage SH, Sonawane KD. Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer’s disease. Neuropeptides 2015; 52: 1–18

[27] Cline EN, Bicca MA, Viola KL, Klein WL. The amyloid-β oligomer hypothesis: beginning of the third decade. J Alzheimers Dis 2018; 64(s1): S567–S610

[28] Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 2016; 8(6): 595–608

[29] Bakota L, Brandt R. Tau biology and tau-directed therapies for Alzheimer’s disease. Drugs 2016; 76(3): 301–313

[30] Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburg CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RYH, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT. Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 2018; 99(5): 925–940.e7

[31] Mirza SS, Wolters FJ, Swanson SA, Koudstaal PJ, Hofman A, Tiemeier H, Ikram MA. 10-year trajectories of depressive symptoms and risk of dementia: a population-based study. Lancet Psychiatry 2016; 3(7): 628–635

[32] Burke AD, Goldfarb D, Bollam P, Khokher S. Diagnosing and treating depression in patients with Alzheimer’s disease. Neurol Ther 2019; 8(2): 325–350

[33] Novais F, Starkstein S. Phenomenology of depression in Alzheimer’s disease. J Alzheimers Dis 2015; 47(4): 845–855

[34] Cobb JA, O’Neill K, Milner J, Mahajan GJ, Lawrence TJ, May WL, Miguel-Hidalgo J, Rajkowska G, Stockmeier CA. Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience 2016; 316: 209–220

[35] Lemoine L, Saint-Aubert L, Nennesmo I, Gillberg PG, Nordberg A. Cortical laminar tau deposits and activated astrocytes in Alzheimer’s disease visualised by ³H-THK5117 and ³H-deprenyl autoradiography. Sci Rep 2017; 7(1): 45496

[36] Arranz AM, De Strooper B. The role of astroglia in Alzheimer’s disease: pathophysiology and clinical implications. Lancet Neurol 2019; 18(4): 406–414

[37] Escartin C, Guillemaud O, Carrillo-de Sauvage MA. Questions and (some) answers on reactive astrocytes. Glia 2019; 67(12): 2221–2247

[38] Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb Blood Flow Metab 2012; 32(7): 1222–1232

[39] Alberini CM, Cruz E, Descalzi G, Bessières B, Gao V. Astrocyte glycogen and lactate: new insights into learning and memory mechanisms. Glia 2018; 66(6): 1244–1262

[40] Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N. Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 2010; 11(2): 87–99

[41] Koepsell H. Glucose transporters in brain in health and disease. Pflugers Arch 2020; 472(9): 1299–1343

[42] Calì C, Tauffenberger A, Magistretti P. The strategic location of glycogen and lactate: from body energy reserve to brain plasticity. Front Cell Neurosci 2019; 13: 82

[43] Magistretti PJ, Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci 2018; 19(4): 235–249

[44] Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SHR, Saudou F, Mattson MP, Swerdlow RH, Millan MJ. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov 2020; 19(9): 609–633

[45] Juaristi I, Contreras L, González-Sánchez P, Pérez-Liébana I, González-Moreno L, Pardo B, Del Arco A, Satrústegui J. The response to stimulation in neurons and astrocytes. Neurochem Res 2019; 44(10): 2385–2391

[46] Barros LF, Brown A, Swanson RA. Glia in brain energy metabolism: a perspective. Glia 2018; 66(6): 1134–1137

[47] Dienel GA. Brain glucose metabolism: integration of energetics with function. Physiol Rev 2019; 99(1): 949–1045

[48] Mächler P, Wyss MT, Elsayed M, Stobart J, Gutierrez R, von Faber-Castell A, Kaelin V, Zuend M, San Martín A, Romero-Gómez I, Baeza-Lehnert F, Lengacher S, Schneider BL, Aebischer P, Magistretti PJ, Barros LF, Weber B. In vivo evidence for a lactate gradient from astrocytes to neurons. Cell Metab 2016; 23(1): 94–102

[49] Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell 2011; 144(5): 810–823

[50] Brooks GA. The science and translation of lactate shuttle theory. Cell Metab 2018; 27(4): 757–785

[51] Detka J, Kurek A, Kucharczyk M, Głombik K, Basta-Kaim A, Kubera M, Lasoń W, Budziszewska B. Brain glucose metabolism in an animal model of depression. Neuroscience 2015; 295: 198–208

[52] Yin YN, Hu J, Wei YL, Li ZL, Luo ZC, Wang RQ, Yang KX, Li SJ, Li XW, Yang JM, Gao TM. Astrocyte-derived lactate modulates the passive coping response to behavioral challenge in male mice. Neurosci Bull 2021; 37(1): 1–14

[53] Murphy-Royal C, Johnston AD, Boyce AKJ, Diaz-Castro B, Institoris A, Peringod G, Zhang O, Stout RF, Spray DC, Thompson RJ, Khakh BS, Bains JS, Gordon GR. Stress gates an astrocytic energy reservoir to impair synaptic plasticity. Nat Commun 2020; 11(1): 2014

[54] Carrard A, Elsayed M, Margineanu M, Boury-Jamot B, Fragnière L, Meylan EM, Petit JM, Fiumelli H, Magistretti PJ, Martin JL. Peripheral administration of lactate produces antidepressant-like effects. Mol Psychiatry 2018; 23(2): 392–399

[55] Yang J, Ruchti E, Petit JM, Jourdain P, Grenningloh G, Allaman I, Magistretti PJ. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons. Proc Natl Acad Sci USA 2014; 111(33): 12228–12233

[56] Powell CL, Davidson AR, Brown AM. Universal glia to neurone lactate transfer in the nervous system: physiological functions and pathological consequences. Biosensors (Basel) 2020; 10(11): E183

[57] Karnib N, El-Ghandour R, El Hayek L, Nasrallah P, Khalifeh M, Barmo N, Jabre V, Ibrahim P, Bilen M, Stephan JS, Holson EB, Ratan RR, Sleiman SF. Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases. Neuropsychopharmacology 2019; 44(6):1152–1162

[58] Bak LK, Walls AB. CrossTalk opposing view: lack of evidence supporting an astrocyte-to-neuron lactate shuttle coupling neuronal activity to glucose utilisation in the brain. J Physiol 2018; 596(3): 351–353

[59] Dienel GA. Lack of appropriate stoichiometry: strong evidence against an energetically important astrocyte-neuron lactate shuttle in brain. J Neurosci Res 2017; 95(11): 2103–2125

[60] Lipmann F. Metabolic Generation and Utilization of Phosphate Bond Energy. John Wiley & Sons, Inc., 2006

[61] Mori M, Heuss C, Gähwiler BH, Gerber U. Fast synaptic transmission mediated by P2X receptors in CA3 pyramidal cells of rat hippocampal slice cultures. J Physiol 2001; 535(1): 115–123

[62] Pankratov Y, Lalo U, Krishtal O, Verkhratsky A. Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex. J Physiol 2002; 542(2): 529–536

[63] Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med 2013; 19(6): 773–777

[64] Bansal Y, Kuhad A. Mitochondrial dysfunction in depression. Curr Neuropharmacol 2016; 14(6): 610–618

[65] Nakamura Y, Park JH, Hayakawa K. Therapeutic use of extracellular mitochondria in CNS injury and disease. Exp Neurol 2020; 324: 113114

[66] Illes P, Rubini P, Yin H, Tang Y. Impaired ATP release from brain astrocytes may be a cause of major depression. Neurosci Bull 2020; 36(11): 1281–1284

[67] Rajani V, Zhang Y, Jalubula V, Rancic V, SheikhBahaei S, Zwicker JD, Pagliardini S, Dickson CT, Ballanyi K, Kasparov S, Gourine AV, Funk GD. Release of ATP by pre-Bötzinger complex astrocytes contributes to the hypoxic ventilatory response via a Ca²⁺-dependent P2Y₁ receptor mechanism. J Physiol 2018; 596(15): 3245–3269

[68] Halassa MM, Fellin T, Haydon PG. Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 2009; 57(4): 343–346

[69] Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, Li ME, Yu R, Kleinridders A, Pothos EN, Kahn CR. Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Invest 2018; 128(7): 2914–2926

[70] Choi W, Clemente N, Sun W, Du J, Lü W. The structures and gating mechanism of human calcium homeostasis modulator 2. Nature 2019; 576(7785): 163–167

[71] Syrjanen JL, Michalski K, Chou TH, Grant T, Rao S, Simorowski N, Tucker SJ, Grigorieff N, Furukawa H. Structure and assembly of calcium homeostasis modulator proteins. Nat Struct Mol Biol 2020; 27(2): 150–159

[72] Ma J, Qi X, Yang C, Pan R, Wang S, Wu J, Huang L, Chen H, Cheng J, Wu R, Liao Y, Mao L, Wang FC, Wu Z, An JX, Wang Y, Zhang X, Zhang C, Yuan Z. Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors. Mol Psychiatry 2018; 23(4): 883–891

[73] Dreses-Werringloer U, Lambert JC, Vingtdeux V, Zhao H, Vais H, Siebert A, Jain A, Koppel J, Rovelet-Lecrux A, Hannequin D, Pasquier F, Galimberti D, Scarpini E, Mann D, Lendon C, Campion D, Amouyel P, Davies P, Foskett JK, Campagne F, Marambaud P. A polymorphism in CALHM1 influences Ca²⁺ homeostasis, Aβ levels, and Alzheimer’s disease risk. Cell 2008; 133(7): 1149–1161

[74] Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A, Adrien L, Zhao H, Leung S, Abernethy M, Koppel J, Davies P, Civan MM, Chaudhari N, Matsumoto I, Hellekant G, Tordoff MG, Marambaud P, Foskett JK. CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes. Nature 2013; 495(7440): 223–226

[75] Rial D, Lemos C, Pinheiro H, Duarte JM, Gonçalves FQ, Real JI, Prediger RD, Gonçalves N, Gomes CA, Canas PM, Agostinho P, Cunha RA. Depression as a glial-based synaptic dysfunction. Front Cell Neurosci 2016; 9: 521

[76] Trautmann A. Extracellular ATP in the immune system: more than just a “danger signal”. Sci Signal 2009; 2(56): pe6

[77] Janks L, Sharma CVR, Egan TM. A central role for P2X7 receptors in human microglia. J Neuroinflammation 2018; 15(1): 325

[78] Iwata M, Ota KT, Li XY, Sakaue F, Li N, Dutheil S, Banasr M, Duric V, Yamanashi T, Kaneko K, Rasmussen K, Glasebrook A, Koester A, Song D, Jones KA, Zorn S, Smagin G, Duman RS. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biol Psychiatry 2016; 80(1): 12–22

[79] Illes P, Verkhratsky A, Tang Y. Pathological ATPergic signaling in major depression and bipolar disorder. Front Mol Neurosci 2020; 12: 331

[80] Farooq RK, Tanti A, Ainouche S, Roger S, Belzung C, Camus V. A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice. Psychoneuroendocrinology 2018; 97: 120–130

[81] Yue N, Huang H, Zhu X, Han Q, Wang Y, Li B, Liu Q, Wu G, Zhang Y, Yu J. Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors. J Neuroinflammation 2017; 14(1): 102

[82] Rodrigues RJ, Tomé AR, Cunha RA. ATP as a multi-target danger signal in the brain. Front Neurosci 2015; 9: 148

[83] Wang C, Yin Q, Su Z, Xia L. Progress on role of extracellular ATP and its metabolite adenosine in immunoregulation: review. Chin J Cell Mol Immunol (Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi) 2020; 36(12):1134–1140 (in Chinese)

[84] Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders—a review. Curr Neurol Neurosci Rep 2017; 17(3): 25

[85] Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: a general review. Int J Neurosci 2017; 127(7): 624–633

[86] Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol 2016; 37(9): 608–620

[87] Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 2004; 24(9): 2143–2155

[88] Myer DJ, Gurkoff GG, Lee SM, Hovda DA, Sofroniew MV. Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 2006; 129(10): 2761–2772

[89] Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S, Sofroniew MV. Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 2009; 29(37): 11511–11522

[90] Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI, Mascanfroni ID, Yeste A, Kivisäkk P, Kallas K, Ellezam B, Bakshi R, Prat A, Antel JP, Weiner HL, Quintana FJ. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 2014; 20(10): 1147–1156

[91] Brites D, Fernandes A. Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci 2015; 9: 476

[92] Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, Brizard B, El Hage W, Surget A, Belzung C, Camus V. Neuroinflammation and depression: a review. Eur J Neurosci 2021; 53(1): 151–171

[93] Cernackova A, Durackova Z, Trebaticka J, Mravec B. Neuroinflammation and depressive disorder: the role of the hypothalamus. J Clin Neurosci 2020; 75: 5–10

[94] Zheng ZH, Tu JL, Li XH, Hua Q, Liu WZ, Liu Y, Pan BX, Hu P, Zhang WH. Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain Behav Immun 2021; 91: 505–518

[95] Ali T, Rahman SU, Hao Q, Li W, Liu Z, Ali Shah F, Murtaza I, Zhang Z, Yang X, Liu G, Li S. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J Pineal Res 2020; 69(2): e12667

[96] Li W, Ali T, He K, Liu Z, Shah FA, Ren Q, Liu Y, Jiang A, Li S. Ibrutinib alleviates LPS-induced neuroinflammation and synaptic defects in a mouse model of depression. Brain Behav Immun 2021; 92: 10–24

[97] Walker AK, Wing EE, Banks WA, Dantzer R. Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. Mol Psychiatry 2019; 24(10): 1523–1532

[98] Zhang Y, Du L, Bai Y, Han B, He C, Gong L, Huang R, Shen L, Chao J, Liu P, Zhang H, Zhang H, Gu L, Li J, Hu G, Xie C, Zhang Z, Yao H. CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination. Mol Psychiatry 2020; 25(6): 1175–1190

[99] Leng L, Zhuang K, Liu Z, Huang C, Gao Y, Chen G, Lin H, Hu Y, Wu D, Shi M, Xie W, Sun H, Shao Z, Li H, Zhang K, Mo W, Huang TY, Xue M, Yuan Z, Zhang X, Bu G, Xu H, Xu Q, Zhang J. Menin deficiency leads to depressive-like behaviors in mice by modulating astrocyte-mediated neuroinflammation. Neuron 2018; 100(3): 551–563.e7

[100] Wu Y, Qiu A, Yang Z, Wu J, Li X, Bao K, Wang M, Wu B. Malva sylvestris extract alleviates the astrogliosis and inflammatory stress in LPS-induced depression mice. J Neuroimmunol 2019; 336: 577029

[101] Wang Y, Ni J, Zhai L, Gao C, Xie L, Zhao L, Yin X. Inhibition of activated astrocyte ameliorates lipopolysaccharide-induced depressive-like behaviors. J Affect Disord 2019; 242: 52–59

[102] Zhang HY, Wang Y, He Y, Wang T, Huang XH, Zhao CM, Zhang L, Li SW, Wang C, Qu YN, Jiang XX. A1 astrocytes contribute to murine depression-like behavior and cognitive dysfunction, which can be alleviated by IL-10 or fluorocitrate treatment. J Neuroinflammation 2020; 17(1): 200

[103] Zimmer ER, Leuzy A, Benedet AL, Breitner J, Gauthier S, Rosa-Neto P. Tracking neuroinflammation in Alzheimer’s disease: the role of positron emission tomography imaging. J Neuroinflammation 2014; 11(1): 120

[104] Frost GR, Li YM. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol 2017; 7(12): 170228

[105] Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019; 15(2): 73–88

[106] Verkhratsky A, Parpura V, Rodriguez-Arellano JJ, Zorec R. Astroglia in Alzheimer’s disease. Adv Exp Med Biol 2019; 1175: 273–324

[107] Serrano-Pozo A, Muzikansky A, Gómez-Isla T, Growdon JH, Betensky RA, Frosch MP, Hyman BT. Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol 2013; 72(6): 462–471

[108] Okabe Y, Takahashi T, Mitsumasu C, Kosai K, Tanaka E, Matsuishi T. Alterations of gene expression and glutamate clearance in astrocytes derived from an MeCP2-null mouse model of Rett syndrome. PLoS One 2012; 7(4): e35354

[109] Tagarelli A, Piro A, Tagarelli G, Lagonia P, Quattrone A. Alois Alzheimer: a hundred years after the discovery of the eponymous disorder. Int J Biomed Sci 2006; 2(2): 196–204

[110] Ahmad MH, Fatima M, Mondal AC. Influence of microglia and astrocyte activation in the neuroinflammatory pathogenesis of Alzheimer’s disease: rational insights for the therapeutic approaches. J Clin Neurosci 2019; 59: 6–11

[111] Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER. Astrocyte biomarkers in Alzheimer’s disease. Trends Mol Med 2019; 25(2): 77–95

[112] Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, Selkoe DJ. Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 2011; 31(18): 6627–6638

[113] Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541(7638): 481–487

[114] Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR. Alzheimer’s disease β-secretase BACE1 is not a neuron-specific enzyme. J Neurochem 2005; 92(2): 226–234

[115] Veeraraghavalu K, Zhang C, Zhang X, Tanzi RE, Sisodia SS. Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of β-amyloid by cells other than excitatory neurons. J Neurosci 2014; 34(10): 3668–3673

[116] Brunello CA, Merezhko M, Uronen RL, Huttunen HJ. Mechanisms of secretion and spreading of pathological tau protein. Cell Mol Life Sci 2020; 77(9): 1721–1744

[117] Gao Y, Tan L, Yu JT, Tan L. Tau in Alzheimer’s disease: mechanisms and therapeutic strategies. Curr Alzheimer Res 2018; 15(3): 283–300

[118] van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci 2020; 21(1): 21–35

[119] Kovacs GG. Astroglia and tau: new perspectives. Front Aging Neurosci 2020; 12: 96

[120] Allen M, Wang X, Serie DJ, Strickland SL, Burgess JD, Koga S, Younkin CS, Nguyen TT, Malphrus KG, Lincoln SJ, Alamprese M, Zhu K, Chang R, Carrasquillo MM, Kouri N, Murray ME, Reddy JS, Funk C, Price ND, Golde TE, Younkin SG, Asmann YW, Crook JE, Dickson DW, Ertekin-Taner N. Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Acta Neuropathol 2018; 136(5): 709–727

[121] Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 2000; 33(1): 95–130

[122] Adams SJ, DeTure MA, McBride M, Dickson DW, Petrucelli L. Three repeat isoforms of tau inhibit assembly of four repeat tau filaments. PLoS One 2010; 5(5): e10810

[123] Richetin K, Steullet P, Pachoud M, Perbet R, Parietti E, Maheswaran M, Eddarkaoui S, Bégard S, Pythoud C, Rey M, Caillierez R, Q Do K, Halliez S, Bezzi P, Buée L, Leuba G, Colin M, Toni N, Déglon N. Tau accumulation in astrocytes of the dentate gyrus induces neuronal dysfunction and memory deficits in Alzheimer’s disease. Nat Neurosci 2020; 23(12): 1567–1579

[124] Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 2018; 562(7728): 578–582

[125] Newington JT, Harris RA, Cumming RC. Reevaluating metabolism in Alzheimer’s disease from the perspective of the astrocyte-neuron lactate shuttle model. J Neurodegener Dis 2013; 2013: 234572

[126] Zhang M, Cheng X, Dang R, Zhang W, Zhang J, Yao Z. Lactate deficit in an Alzheimer disease mouse model: the relationship with neuronal damage. J Neuropathol Exp Neurol 2018; 77(12): 1163–1176

[127] Pal S, Paul S. ATP controls the aggregation of Aβ_16-22 peptides. J Phys Chem B 2020; 124(1): 210–223

[128] Jung ES, An K, Hong HS, Kim JH, Mook-Jung I. Astrocyte-originated ATP protects Aβ(1-42)-induced impairment of synaptic plasticity. J Neurosci 2012; 32(9): 3081–3087

[129] Park JC, Han SH, Mook-Jung I. Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review. BMB Rep 2020; 53(1): 10–19

[130] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T, Vitorica J, Ransohoff RM, Herrup K, Frautschy SA, Finsen B, Brown GC, Verkhratsky A, Yamanaka K, Koistinaho J, Latz E, Halle A, Petzold GC, Town T, Morgan D, Shinohara ML, Perry VH, Holmes C, Bazan NG, Brooks DJ, Hunot S, Joseph B, Deigendesch N, Garaschuk O, Boddeke E, Dinarello CA, Breitner JC, Cole GM, Golenbock DT, Kummer MP. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015; 14(4): 388–405

[131] Fakhoury M. Microglia and astrocytes in Alzheimer’s disease: implications for therapy. Curr Neuropharmacol 2018; 16(5): 508–518

[132] Pereira CF, Santos AE, Moreira PI, Pereira AC, Sousa FJ, Cardoso SM, Cruz MT. Is Alzheimer’s disease an inflammasomopathy? Ageing Res Rev 2019; 56: 100966

[133] Kaur D, Sharma V, Deshmukh R. Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease. Inflammopharmacology 2019; 27(4): 663–677

[134] Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci 2012; 32(46): 16129–16140

[135] Katsouri L, Birch AM, Renziehausen AWJ, Zach C, Aman Y, Steeds H, Bonsu A, Palmer EOC, Mirzaei N, Ries M, Sastre M. Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer’s disease. Glia 2020; 68(5): 1017–1030

[136] Shu X, Sun Y, Sun X, Zhou Y, Bian Y, Shu Z, Ding J, Lu M, Hu G. The effect of fluoxetine on astrocyte autophagy flux and injured mitochondria clearance in a mouse model of depression. Cell Death Dis 2019; 10(8): 577

[137] Belujon P, Grace AA. Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol 2017; 20(12): 1036–1046

[138] Koppel I, Jaanson K, Klasche A, Tuvikene J, Tiirik T, Pärn A, Timmusk T. Dopamine cross-reacts with adrenoreceptors in cortical astrocytes to induce BDNF expression, CREB signaling and morphological transformation. Glia 2018; 66(1): 206–216

[139] Shao W, Zhang SZ, Tang M, Zhang XH, Zhou Z, Yin YQ, Zhou QB, Huang YY, Liu YJ, Wawrousek E, Chen T, Li SB, Xu M, Zhou JN, Hu G, Zhou JW. Suppression of neuroinflammation by astrocytic dopamine D2 receptors via αB-crystallin. Nature 2013; 494(7435): 90–94

[140] Shimizu M, Nishida A, Zensho H, Yamawaki S. Chronic antidepressant exposure enhances 5-hydroxytryptamine7 receptor-mediated cyclic adenosine monophosphate accumulation in rat frontocortical astrocytes. J Pharmacol Exp Ther 1996; 279(3): 1551–1558

[141] Whitaker-Azmitia PM, Clarke C, Azmitia EC. Localization of 5-HT1A receptors to astroglial cells in adult rats: implications for neuronal-glial interactions and psychoactive drug mechanism of action. Synapse 1993; 14(3): 201–205

[142] Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, Quintana R, Rothwell PE, Lujan R, Marsicano G, Martin ED, Thomas MJ, Kofuji P, Araque A. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron 2020; 105(6): 1036–1047.e5

[143] Inazu M, Takeda H, Ikoshi H, Sugisawa M, Uchida Y, Matsumiya T. Pharmacological characterization and visualization of the glial serotonin transporter. Neurochem Int 2001; 39(1): 39–49

[144] Zhou X, Xiao Q, Xie L, Yang F, Wang L, Tu J. Astrocyte, a promising target for mood disorder interventions. Front Mol Neurosci 2019; 12: 136

[145] Kinoshita M, Hirayama Y, Fujishita K, Shibata K, Shinozaki Y, Shigetomi E, Takeda A, Le HPN, Hayashi H, Hiasa M, Moriyama Y, Ikenaka K, Tanaka KF, Koizumi S. Anti-depressant fluoxetine reveals its therapeutic effect via astrocytes. EBioMedicine 2018; 32: 72–83

[146] Park YM, Lee BH. Alterations in serum BDNF and GDNF levels after 12 weeks of antidepressant treatment in female outpatients with major depressive disorder. Psychiatry Investig 2018; 15(8): 818–823

[147] Niwa M, Nitta A, Yamada Y, Nakajima A, Saito K, Seishima M, Shen L, Noda Y, Furukawa S, Nabeshima T. An inducer for glial cell line-derived neurotrophic factor and tumor necrosis factor-α protects against methamphetamine-induced rewarding effects and sensitization. Biol Psychiatry 2007; 61(7): 890–901

[148] Lu L, Wang X, Wu P, Xu C, Zhao M, Morales M, Harvey BK, Hoffer BJ, Shaham Y. Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol Psychiatry 2009; 66(2): 137–145

[149] Fisher JR, Wallace CE, Tripoli DL, Sheline YI, Cirrito JR. Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo. Mol Neurodegener 2016; 11(1): 45

[150] Ma J, Gao Y, Jiang L, Chao FL, Huang W, Zhou CN, Tang W, Zhang L, Huang CX, Zhang Y, Luo YM, Xiao Q, Yu HR, Jiang R, Tang Y. Fluoxetine attenuates the impairment of spatial learning ability and prevents neuron loss in middle-aged APPswe/PSEN1dE9 double transgenic Alzheimer’s disease mice. Oncotarget 2017; 8(17): 27676–27692

[151] Zhou CN, Chao FL, Zhang Y, Jiang L, Zhang L, Fan JH, Wu YX, Dou XY, Tang Y. Fluoxetine delays the cognitive function decline and synaptic changes in a transgenic mouse model of early Alzheimer’s disease. J Comp Neurol 2019; 527(8): 1378–1387

[152] Alexopoulos GS. Mechanisms and treatment of late-life depression. Transl Psychiatry 2019; 9(1): 188

[153] Grace AA. Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression. Nat Rev Neurosci 2016; 17(8): 524–532

[154] Pytka K, Podkowa K, Rapacz A, Podkowa A, Żmudzka E, Olczyk A, Sapa J, Filipek B. The role of serotonergic, adrenergic and dopaminergic receptors in antidepressant-like effect. Pharmacol Rep 2016; 68(2): 263–274

[155] Kumar U, Patel SC. Immunohistochemical localization of dopamine receptor subtypes (D1R-D5R) in Alzheimer’s disease brain. Brain Res 2007; 1131(1): 187–196

[156] Pan X, Kaminga AC, Wen SW, Wu X, Acheampong K, Liu A. Dopamine and dopamine receptors in Alzheimer’s disease: a systematic review and network meta-analysis. Front Aging Neurosci 2019; 11: 175

[157] Koch G, Di Lorenzo F, Bonnì S, Giacobbe V, Bozzali M, Caltagirone C, Martorana A. Dopaminergic modulation of cortical plasticity in Alzheimer’s disease patients. Neuropsychopharmacology. 2014; 39(11): 2654–2661

[158] D’Amelio M, Puglisi-Allegra S, Mercuri N. The role of dopaminergic midbrain in Alzheimer’s disease: translating basic science into clinical practice. Pharmacol Res 2018; 130: 414–419

[159] Krashia P, Nobili A, D’Amelio M. Unifying hypothesis of dopamine neuron loss in neurodegenerative diseases: focusing on Alzheimer’s disease. Front Mol Neurosci 2019; 12: 123

[160] Jha MK, Jo M, Kim JH, Suk K. Microglia-astrocyte crosstalk: an intimate molecular conversation. Neuroscientist 2019; 25(3): 227–240

[161] Molofsky AV, Deneen B. Astrocyte development: a guide for the perplexed. Glia 2015; 63(8): 1320–1329

[162] Herbert J, Lucassen PJ. Depression as a risk factor for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis—what do we need to know? Front Neuroendocrinol 2016; 41: 153–171

[163] Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006; 63(5): 530–538

[164] Barlinn K, Kepplinger J, Puetz V, Illigens BM, Bodechtel U, Siepmann T. Exploring the risk-factor association between depression and incident stroke: a systematic review and meta-analysis. Neuropsychiatr Dis Treat 2014; 11: 1–14

[165] Gan Y, Gong Y, Tong X, Sun H, Cong Y, Dong X, Wang Y, Xu X, Yin X, Deng J, Li L, Cao S, Lu Z. Depression and the risk of coronary heart disease: a meta-analysis of prospective cohort studies. BMC Psychiatry 2014; 14(1): 371

[166] Troubat R, Barone P, Leman S, Desmidt T, Cressant A, Atanasova B, Brizard B, El Hage W, Surget A, Belzung C, Camus V. Neuroinflammation and depression: a review. Eur J Neurosci 2021; 53(1): 151–171

[167] Uddin MS, Kabir MT, Rahman MS, Behl T, Jeandet P, Ashraf GM, Najda A, Bin-Jumah MN, El-Seedi HR, Abdel-Daim MM. Revisiting the amyloid cascade hypothesis: from anti-Aβ therapeutics to auspicious new ways for Alzheimer’s disease. Int J Mol Sci 2020; 21(16): E5858

[168] Wang Q, Jie W, Liu JH, Yang JM, Gao TM. An astroglial basis of major depressive disorder? An overview. Glia 2017; 65(8): 1227–1250

[169] Han X, Chen M, Wang F, Windrem M, Wang S, Shanz S, Xu Q, Oberheim NA, Bekar L, Betstadt S, Silva AJ, Takano T, Goldman SA, Nedergaard M. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 2013; 12(3): 342–353

[170] Lepore AC, Rauck B, Dejea C, Pardo AC, Rao MS, Rothstein JD, Maragakis NJ. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat Neurosci 2008; 11(11): 1294–1301

[171] Qian H, Kang X, Hu J, Zhang D, Liang Z, Meng F, Zhang X, Xue Y, Maimon R, Dowdy SF, Devaraj NK, Zhou Z, Mobley WC, Cleveland DW, Fu XD. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature 2020; 582(7813): 550–556

[172] Zhou H, Su J, Hu X, Zhou C, Li H, Chen Z, Xiao Q, Wang B, Wu W, Sun Y, Zhou Y, Tang C, Liu F, Wang L, Feng C, Liu M, Li S, Zhang Y, Xu H, Yao H, Shi L, Yang H. Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice. Cell 2020; 181(3): 590–603.e16

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