Skip to main content

Advertisement

SpringerLink
Log in

As a Potential Therapeutic Target, C1q Induces Synapse Loss Via Inflammasome-activating Apoptotic and Mitochondria Impairment Mechanisms in Alzheimer’s Disease

  • INVITED REVIEW
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

C1q, the initiator of the classical pathway of the complement system, is activated during Alzheimer’s disease (AD) development and progression and is especially associated with the production and deposition of β-amyloid protein (Aβ) and phosphorylated tau in β-amyloid plaques (APs) and neurofibrillary tangles (NFTs). Activation of C1q is responsible for induction of synapse loss, leading to neurodegeneration in AD. Mechanistically, C1q could activate glial cells, which results in the loss of synapses via regulation of synapse pruning and phagocytosis in AD. In addition, C1q induces neuroinflammation by inducing proinflammatory cytokine secretion, which is partially mediated by inflammasome activation. Activation of inflammasomes might mediate the effects of C1q on induction of synapse apoptosis. On the other hand, activation of C1q impairs mitochondria, which hinders the renovation and regeneration of synapses. All these actions of C1q contribute to the loss of synapses during neurodegeneration in AD. Therefore, pharmacological, or genetic interventions targeting C1q may provide potential therapeutic strategies for combating AD.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

References

  • Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ (1996) Localization and cell association of C1q in Alzheimer’s disease brain. Exp Neurol 138:22–32

    Article  CAS  PubMed  Google Scholar 

  • Aleksandra V, Nicolas D, Fletcher EV, Pagiazitis JG, Sethu S, Yednock TA, Barres BA, Mentis GZ (2020) The Classical Complement Pathway Mediates Microglia-Dependent Remodeling of Spinal Motor Circuits during Development and in SMA. Cell Rep 29:3087–3100

    Google Scholar 

  • Alves S, Churlaud G, Audrain M, Michaelsen-Preusse K, Fol R, Souchet B, Braudeau J, Korte M, Klatzmann D, Cartier N (2017) Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice. Brain : a Journal of Neurology 140:826–842

    PubMed  Google Scholar 

  • Arrázola MS, Andraini T, Szelechowski M, Mouledous L, Arnauné-Pelloquin L, Davezac N, Belenguer P, Rampon C, Miquel MC (2019) Mitochondria in Developmental and Adult Neurogenesis. Neurotox Res 36:257–267

    Article  PubMed  Google Scholar 

  • Audrain M, Haure-Mirande JV, Wang M, Kim SH, Fanutza T, Chakrabarty P, Fraser P, St George-Hyslop PH, Golde TE, Blitzer RD, Schadt EE, Zhang B, Ehrlich ME, Gandy S (2019) Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau. Mol Psychiatry 24:1383–1397

    Article  CAS  PubMed  Google Scholar 

  • Batista AF, Rody T, Forny-Germano L, Cerdeiro S, Bellio M, Ferreira ST, Munoz DP, De Felice FG (2021) Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers. J Neuroinflammation 18:54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benoit ME, Hernandez MX, Dinh ML, Benavente F, Vasquez O, Tenner AJ (2013) C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-β neurotoxicity. J Biol Chem 288:654–665

    Article  CAS  PubMed  Google Scholar 

  • Bergamaschini L, Canziani S, Bottasso B, Cugno M, Braidotti P, Agostoni A (1999) Alzheimer’s beta-amyloid peptides can activate the early components of complement classical pathway in a C1q-independent manner. Clin Exp Immunol 115:526–533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bie B, Wu J, Foss JF, Naguib M (2019) Activation of mGluR1 Mediates C1q-Dependent Microglial Phagocytosis of Glutamatergic Synapses in Alzheimer’s Rodent Models. Mol Neurobiol 56:5568–5585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brazil MI, Chung H, Maxfield FR (2000) Effects of incorporation of immunoglobulin G and complement component C1q on uptake and degradation of Alzheimer’s disease amyloid fibrils by microglia. J Biol Chem 275:16941–16947

    Article  CAS  PubMed  Google Scholar 

  • Brigas HC, Ribeiro M, Coelho JE, Gomes R, Gomez-Murcia V, Carvalho K, Faivre E, Costa-Pereira S, Darrigues J, de Almeida AA, Buée L, Dunot J, Marie H, Pousinha PA, Blum D, Silva-Santos B, Lopes LV, Ribot JC (2021) IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer’s disease. Cell Rep 36:109574

    Article  CAS  PubMed  Google Scholar 

  • Brill M, Kleele T, Ruschkies L, Wang M, Misgeld T (2016) Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination. Neuron 92:845–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brunetti D, Dykstra W, Le S, Zink A, Prigione A (2021) Mitochondria in neurogenesis: Implications for mitochondrial diseases. Stem Cells (dayton, Ohio) 39:1289–1297

    Article  CAS  PubMed  Google Scholar 

  • Carvalho K et al (2019) Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor. Brain J Neurol 142:3636–3654

    Article  Google Scholar 

  • Cho KJ, Cheon SY, Kim GW (2016) Apoptosis signal-regulating kinase 1 mediates striatal degeneration via the regulation of C1q. Sci Rep 6:18840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA (2016) Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci USA 113:10186–10191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Comis A, Easterbrook-Smith SB (1985) C1q binding to mitochondria: a possible artefact? FEBS Lett 185:105–108

    Article  CAS  PubMed  Google Scholar 

  • Cornell J, Salinas S, Huang HY, Zhou M (2022) Microglia regulation of synaptic plasticity and learning and memory. Neural Regen Res 17:705–716

    Article  CAS  PubMed  Google Scholar 

  • Czirr E, Castello NA, Mosher KI, Castellano JM, Hinkson IV, Lucin KM, Baeza-Raja B, Ryu JK, Li L, Farina SN, Belichenko NP, Longo FM, Akassoglou K, Britschgi M, Cirrito JR, Wyss-Coray T (2017) Microglial complement receptor 3 regulates brain Abeta levels through secreted proteolytic activity. J Exp Med 214:1081–1092

    Article  PubMed  PubMed Central  Google Scholar 

  • Datta D, Leslie SN, Morozov YM, Duque A, Rakic P, van Dyck CH, Nairn AC, Arnsten AFT (2020) Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex. J Neuroinflammation 17:8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Drose S, Brandt U, Muller WE, Eckert A, Gotz J (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280:23802–23814

    Article  CAS  PubMed  Google Scholar 

  • De Strooper B, Karran E (2016) The Cellular Phase of Alzheimer’s Disease. Cell 164:603–615

    Article  PubMed  Google Scholar 

  • Dedio J, Jahnen-Dechent W, Bachmann M, Müller-Esterl W (1998) The multiligand-binding protein gC1qR, putative C1q receptor, is a mitochondrial protein. J Immunol (Baltimore, Md : 1950) 160:3534–3542

  • Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T, Srinivasan K, Jiang Z, Gandham V, Friedman BA, Ngu H, Foreman O, Carano RAD, Chih B, Klumperman J, Bakalarski C, Hanson JE, Sheng M (2018) Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron 100:1322-1336.e1327

    Article  CAS  PubMed  Google Scholar 

  • Delgado-Peraza F, Nogueras-Ortiz CJ, Volpert O, Liu D, Goetzl EJ, Mattson MP, Greig NH, Eitan E, Kapogiannis D (2021) Neuronal and astrocytic extracellular vesicle biomarkers in blood reflect brain pathology in mouse models of alzheimer's disease. Cells 10

  • Du H, Guo L, Yan SS (2012) Synaptic mitochondrial pathology in Alzheimer’s disease. Antioxid Redox Signal 16:1467–1475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eikelenboom P, Veerhuis R, Familian A, Hoozemans JJ, van Gool WA, Rozemuller AJ (2008) Neuroinflammation in plaque and vascular beta-amyloid disorders: clinical and therapeutic implications. Neurodegener Dis 5:190–193

    Article  CAS  PubMed  Google Scholar 

  • Familian A, Boshuizen RS, Eikelenboom P, Veerhuis R (2006) Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation. Glia 53:233–240

    Article  PubMed  Google Scholar 

  • Fan R, DeFilippis K, Van Nostrand WE (2007) Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition. J Neuroinflammation 4:22

    Article  PubMed  PubMed Central  Google Scholar 

  • Fan R, Tenner AJ (2004) Complement C1q expression induced by Abeta in rat hippocampal organotypic slice cultures. Exp Neurol 185:241–253

    Article  CAS  PubMed  Google Scholar 

  • Fernandez A, Meechan DW, Karpinski BA, Paronett EM, Bryan CA, Rutz HL, Radin EA, Lubin N, Bonner ER, Popratiloff A, Rothblat LA, Maynard TM, LaMantia A-S (2019) Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment. Neuron 102:1127–1142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fonseca MI, Chu SH, Berci AM, Benoit ME, Peters DG, Kimura Y, Tenner AJ (2011) Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer’s disease. J Neuroinflammation 8:4

    Article  PubMed  PubMed Central  Google Scholar 

  • Fonseca MI, Chu SH, Hernandez MX, Fang MJ, Modarresi L, Selvan P, MacGregor GR, Tenner AJ (2017) Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflammation 14:48

    Article  PubMed  PubMed Central  Google Scholar 

  • Fraser DA, Pisalyaput K, Tenner AJ (2010) C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem 112:733–743

    Article  CAS  PubMed  Google Scholar 

  • Gewurz H, Ying SC, Jiang H, Lint TF (1993) Nonimmune activation of the classical complement pathway. Behring Institute Mitteilungen 138–147

  • Goetzl EJ, Schwartz JB, Abner EL, Jicha GA, Kapogiannis D (2018) High complement levels in astrocyte-derived exosomes of Alzheimer disease. Ann Neurol 83:544–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Arboledas A, Acharya MM, Tenner AJ (2021) The Role of Complement in Synaptic Pruning and Neurodegeneration. ImmunoTargets Ther 10:373–386

    Article  PubMed  PubMed Central  Google Scholar 

  • Györffy BA, Kun J, Török G, Bulyáki É, Borhegyi Z, Gulyássy P, Kis V, Szocsics P, Micsonai A, Matkó J, Drahos L, Juhász G, Kékesi KA, Kardos J (2018) Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning. Proc Natl Acad Sci USA 115:6303–6308

    Article  PubMed  PubMed Central  Google Scholar 

  • Györffy BA, Tóth V, Török G, Gulyássy P, Kovács R, Vadászi H, Micsonai A, Tóth ME, Sántha M, Homolya L, Drahos L, Juhász G, Kékesi KA, Kardos J (2020) Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model. Cell Mol Life Sci 77:5243–5258

    Article  PubMed  PubMed Central  Google Scholar 

  • Habib A, Sawmiller D, Hou H, Kanithi M, Tian J, Zeng J, Zi D, He ZX, Sanberg PR, Tan J (2018) Human Cord Blood Serum-Derived APP α-Secretase Cleavage Activity is Mediated by C1 Complement. Cell Transplant 27:666–676

    Article  PubMed  PubMed Central  Google Scholar 

  • Han SM, Baig HS, Hammarlund M (2016) Mitochondria Localize to Injured Axons to Support Regeneration. Neuron 92:1308–1323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hao X, Li Z, Li W, Katz J, Michalek SM, Barnum SR, Pozzo-Miller L, Saito T, Saido TC, Wang Q, Roberson ED, Zhang P (2022) Periodontal Infection Aggravates C1q-Mediated Microglial Activation and Synapse Pruning in Alzheimer’s Mice. Front Immunol 13:816640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Head E, Azizeh BY, Lott IT, Tenner AJ, Cotman CW, Cribbs DH (2001) Complement association with neurons and beta-amyloid deposition in the brains of aged individuals with Down Syndrome. Neurobiol Dis 8:252–265

    Article  CAS  PubMed  Google Scholar 

  • Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science (new York, NY) 352:712–716

    Article  CAS  Google Scholar 

  • Hoos MD, Richardson BM, Foster MW, Everhart A, Thompson JW, Moseley MA, Colton CA (2013) Longitudinal study of differential protein expression in an Alzheimer’s mouse model lacking inducible nitric oxide synthase. J Proteome Res 12:4462–4477

    Article  CAS  PubMed  Google Scholar 

  • Hua JY, Smith SJ (2004) Neural activity and the dynamics of central nervous system development. Nat Neurosci 7:327–332

    Article  CAS  PubMed  Google Scholar 

  • Iram T, Trudler D, Kain D, Kanner S, Galron R, Vassar R, Barzilai A, Blinder P, Fishelson Z, Frenkel D (2016) Astrocytes from old Alzheimer’s disease mice are impaired in Aβ uptake and in neuroprotection. Neurobiol Dis 96:84–94

    Article  CAS  PubMed  Google Scholar 

  • Iwata R, Vanderhaeghen P (2021) Regulatory roles of mitochondria and metabolism in neurogenesis. Curr Opin Neurobiol 69:231–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • John A, Reddy PH (2021) Synaptic basis of Alzheimer’s disease: Focus on synaptic amyloid beta. P-Tau Mitochondria Ageing Res Rev 65

    Article  CAS  PubMed  Google Scholar 

  • Katz LC, Shatz CJ (1996) Synaptic activity and the construction of cortical circuits. Science 274:1133–1138

    Article  CAS  PubMed  Google Scholar 

  • Keenan BT, Shulman JM, Chibnik LB, Raj T, Tran D, Sabuncu MR, Allen AN, Corneveaux JJ, Hardy JA, Huentelman MJ, Lemere CA, Myers AJ, Nicholson-Weller A, Reiman EM, Evans DA, Bennett DA, De Jager PL (2012) A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline. Hum Mol Genet 21:2377–2388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kishore U, Reid KB (2000) C1q: structure, function, and receptors. Immunopharmacology 49:159–170

    Article  CAS  PubMed  Google Scholar 

  • Kovács R, Vadászi H, Bulyáki É, Török G, Tóth V, Mátyás D, Kun J, Hunyadi-Gulyás É, Fedor FZ, Csincsi Á, Medzihradszky K, Homolya L, Juhász G, Kékesi KA, Józsi M, Györffy BA, Kardos J (2020) Identification of Neuronal Pentraxins as Synaptic Binding Partners of C1q and the Involvement of NP1 in Synaptic Pruning in Adult Mice. Front Immunol 11:599771

    Article  PubMed  Google Scholar 

  • Krukowski K, Chou A, Feng X, Tiret B, Paladini MS, Riparip LK, Chaumeil MM, Lemere C, Rosi S (2018) Traumatic brain injury in aged mice induces chronic microglia activation, synapse loss, and complement-dependent memory deficits. Int J Mol Sci 19

  • Lall D, Lorenzini I, Mota TA, Bell S, Baloh RH (2021a) C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 109:2275–2291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lall D, Lorenzini I, Mota TA, Bell S, Mahan TE, Ulrich JD, Davtyan H, Rexach JE, Muhammad A, Shelest O, Landeros J, Vazquez M, Kim J, Ghaffari L, O’Rourke JG, Geschwind DH, Blurton-Jones M, Holtzman DM, Sattler R, Baloh RH (2021b) C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron 109:2275-2291.e2278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LaRocca TJ, Cavalier AN, Roberts CM, Lemieux MR, Ramesh P, Garcia MA, Link CD (2021) Amyloid beta acts synergistically as a pro-inflammatory cytokine. Neurobiol Dis 159:105493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lehrman EK, Wilton DK, Litvina EY, Welsh CA, Chang ST, Frouin A, Walker AJ, Heller MD, Umemori H, Chen C, Stevens B (2018) CD47 Protects Synapses from Excess Microglia-Mediated Pruning during Development. Neuron 100:120–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li AD, Tong L, Xu N, Ye Y, Nie PY, Wang ZY, Ji LL (2019a) miR-124 regulates cerebromicrovascular function in APP/PS1 transgenic mice via C1ql3. Brain Res Bull 153:214–222

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Severance EG, Viscidi RP, Yolken RH, Xiao J (2019b) Persistent Toxoplasma Infection of the Brain Induced Neurodegeneration Associated with Activation of Complement and Microglia. Infect Immun 87

  • Liang J, Ning Y, Dong L, Ma X, Li S, Yang H, Li Q, Chen L, Gao L, Xu Y (2020) The role of the globular heads of the C1q receptor in TcdA-induced human colonic epithelial cell apoptosis via a mitochondria-dependent pathway. BMC Microbiol 20:274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, Wang Q, Zhang B, Liu Z, Zheng H (2018) Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease. Neuron 100:1337–1353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez-Sanchez C, Garcia-Martinez V, Poejo J, Garcia-Lopez V, Salazar J, Gutierrez-Merino C (2020) Early Reactive A1 Astrocytes Induction by the Neurotoxin 3-Nitropropionic Acid in Rat Brain. Int J Mol Sci 21

  • Luchena C, Zuazo-Ibarra J, Alberdi E, Matute C, Capetillo-Zarate E (2018) Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer’s Disease. Mediators Inflamm 2018:2530414

    Article  PubMed  PubMed Central  Google Scholar 

  • Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM Jr, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J (2001) Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia 35:72–79

    Article  CAS  PubMed  Google Scholar 

  • Lui H et al (2016) Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation. Cell 165:921–935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo X, Weber GA, Zheng J, Gendelman HE, Ikezu T (2003) C1q-calreticulin induced oxidative neurotoxicity: relevance for the neuropathogenesis of Alzheimer’s disease. J Neuroimmunol 135:62–71

    Article  CAS  PubMed  Google Scholar 

  • Lv KT, Gao LJ, Hua X, Li F, Gu Y, Wang W (2018) The role of the globular heads of the C1q receptor in paclitaxel-induced human ovarian cancer cells apoptosis by a mitochondria-dependent pathway. Anticancer Drugs 29:107–117

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, Olschowka JA, Fonseca MI, O’Banion MK, Tenner AJ, Lemere CA, Duff K (2001) Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 158:1345–1354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan TE, Rozovsky I, Sarkar DK, Young-Chan CS, Nichols NR, Laping NJ, Finch CE (2000) Transforming growth factor-beta1 induces transforming growth factor-beta1 and transforming growth factor-beta receptor messenger RNAs and reduces complement C1qB messenger RNA in rat brain microglia. Neuroscience 101:313–321

    Article  CAS  PubMed  Google Scholar 

  • Morton H, Kshirsagar S, Orlov E, Bunquin LE, Sawant N, Boleng L, George M, Basu T, Ramasubramanian B, Pradeepkiran JA, Kumar S, Vijayan M, Reddy AP, Reddy PH (2021) Defective mitophagy and synaptic degeneration in Alzheimer’s disease: Focus on aging, mitochondria and synapse. Free Radical Biol Med 172:652–667

    Article  CAS  Google Scholar 

  • Mulder SD, Nielsen HM, Blankenstein MA, Eikelenboom P, Veerhuis R (2014) Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro. Glia 62:493–503

    Article  PubMed  Google Scholar 

  • Nguyen PT, Dorman LC, Pan S, Vainchtein ID, Han RT, Nakao-Inoue H, Taloma SE, Barron JJ, Molofsky AB, Kheirbek MA, Molofsky AV (2020) Microglial Remodeling of the Extracellular Matrix Promotes Synapse Plasticity. Cell 182:388–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen HM, Mulder SD, Beliën JA, Musters RJ, Eikelenboom P, Veerhuis R (2010) Astrocytic A beta 1–42 uptake is determined by A beta-aggregation state and the presence of amyloid-associated proteins. Glia 58:1235–1246

    Article  PubMed  Google Scholar 

  • Nonaka S, Nakanishi H (2019) Microglial clearance of focal apoptotic synapses. Neurosci Lett 707:134317

    Article  CAS  PubMed  Google Scholar 

  • Paolicelli RC, Jawaid A, Henstridge CM, Valeri A, Merlini M, Robinson JL, Lee EB, Rose J, Appel S, Lee VMY, Trojanowski JQ, Spires-Jones T, Schulz PE, Rajendran L (2017) TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron 95:297–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park CH, Lee HS, Kwak MS, Shin JS (2021) Inflammasome-Dependent Peroxiredoxin 2 Secretion Induces the Classical Complement Pathway Activation. Immune Network 21:e36

    Article  PubMed  PubMed Central  Google Scholar 

  • Pasinetti GM, Johnson SA, Rozovsky I, Lampert-Etchells M, Morgan DG, Gordon MN, Morgan TE, Willoughby D, Finch CE (1992) Complement C1qB and C4 mRNAs responses to lesioning in rat brain. Exp Neurol 118:117–125

    Article  CAS  PubMed  Google Scholar 

  • Perez-Nievas BG, Johnson L, Beltran-Lobo P, Hughes MM, Gammallieri L, Tarsitano F, Myszczynska MA, Vazquez-Villasenor I, Jimenez-Sanchez M, Troakes C, Wharton SB, Ferraiuolo L, Noble W (2021) Astrocytic C-X-C motif chemokine ligand-1 mediates β-amyloid-induced synaptotoxicity. J Neuroinflammation 18:306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pisalyaput K, Tenner AJ (2008) Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem 104:696–707

    Article  CAS  PubMed  Google Scholar 

  • Pooler AM, Noble W, Hanger DP (2014) A role for tau at the synapse in Alzheimer's disease pathogenesis. Neuropharmacology 76 Pt A:1–8

  • Pradeepkiran JA, Reddy PH (2020) Defective mitophagy in Alzheimer’s disease. Ageing Res Rev 64:101191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rawat P, Teodorof-Diedrich C, Spector SA (2019) Human immunodeficiency virus Type-1 single-stranded RNA activates the NLRP3 inflammasome and impairs autophagic clearance of damaged mitochondria in human microglia. Glia 67:802–824

    Article  PubMed  Google Scholar 

  • Reddy AP, Reddy PH (2017) Mitochondria-Targeted Molecules as Potential Drugs to Treat Patients With Alzheimer’s Disease. Prog Mol Biol Transl Sci 146:173–201

    Article  CAS  PubMed  Google Scholar 

  • Reddy PH, Yin X, Manczak M, Kumar S, Pradeepkiran JA, Vijayan M, Reddy AP (2018) Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer’s disease. Hum Mol Genet 27:2502–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roy ER, Wang B, Wan YW, Chiu G, Cole A, Yin Z, Propson NE, Xu Y, Jankowsky JL, Liu Z, Lee VM, Trojanowski JQ, Ginsberg SD, Butovsky O, Zheng H, Cao W (2020) Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J Clin Investig 130:1912–1930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Samstad EO, Niyonzima N, Nymo S, Aune MH, Ryan L, Bakke SS, Lappegård KT, Brekke OL, Lambris JD, Damås JK, Latz E, Mollnes TE, Espevik T (2014) Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release. J Immunol (Baltimore, Md:1950) 192:2837–2845

  • Sanes JR, Lichtman JW (1999) Development of the vertebrate neuromuscular junction. Annu Rev Neurosci 22:389–442

    Article  CAS  PubMed  Google Scholar 

  • Sárvári M, Vágó I, Wéber CS, Nagy J, Gál P, Mák M, Kósa JP, Závodszky P, Pázmány T (2003) Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity. J Neuroimmunol 137:12–18

    Article  PubMed  Google Scholar 

  • Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM (2021) Alzheimer’s disease. Lancet (london, England) 397:1577–1590

    Article  CAS  PubMed  Google Scholar 

  • Schulz KL, Eckert A, Rhein V, Mai S, Haase W, Reichert AS, Jendrach M, Muller WE, Leuner K (2012) A new link to mitochondrial impairment in tauopathies. Mol Neurobiol 46:205–216

    Article  CAS  PubMed  Google Scholar 

  • Sellar GC, Blake DJ, Reid KB (1991) Characterization and organization of the genes encoding the A-, B- and C-chains of human complement subcomponent C1q. The complete derived amino acid sequence of human C1q. Biochem J 274( Pt 2):481–490

  • Shen Y, Halperin JA, Benzaquen L, Lee CM (1997) Characterization of neuronal cell death induced by complement activation. Brain Res Brain Res Protoc 1:186–194

    Article  CAS  PubMed  Google Scholar 

  • Shen Y, Sullivan T, Lee CM, Meri S, Shiosaki K, Lin CW (1998) Induced expression of neuronal membrane attack complex and cell death by Alzheimer’s beta-amyloid peptide. Brain Res 796:187–197

    Article  CAS  PubMed  Google Scholar 

  • Sheppard O, Coleman MP, Durrant CS (2019) Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. J Neuroinflammation 16:106

    Article  PubMed  PubMed Central  Google Scholar 

  • Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B, Lemere CA (2017) Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci Transl Med 9:eaaf6295

  • Smyth MD, Cribbs DH, Tenner AJ, Shankle WR, Dick M, Kesslak JP, Cotman CW (1994) Decreased levels of C1q in cerebrospinal fluid of living Alzheimer patients correlate with disease state. Neurobiol Aging 15:609–614

    Article  CAS  PubMed  Google Scholar 

  • Soininen H, Heinonen O, Hallikainen M, Hänninen T, Koivisto K, Syrjänen S, Talasniemi S, Riekkinen PJ Sr (1993) Circulating immune complexes in sera from patients with Alzheimer’s disease and subjects with age-associated memory impairment. J Neural Transm Park Dis Dement Sect 6:179–188

    Article  CAS  PubMed  Google Scholar 

  • Spielman L, Winger D, Ho L, Aisen PS, Shohami E, Pasinetti GM (2002) Induction of the complement component C1qB in brain of transgenic mice with neuronal overexpression of human cyclooxygenase-2. Acta Neuropathol 103:157–162

    Article  CAS  PubMed  Google Scholar 

  • Spires-Jones TL, Hyman BT (2014) The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron 82:756–771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stephan AH, Barres BA, Stevens B (2012) The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci 35:369–389

    Article  CAS  PubMed  Google Scholar 

  • Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    Article  CAS  PubMed  Google Scholar 

  • Storrs SB, Kolb WP, Pinckard RN, Olson MS (1981) Characterization of the binding of purified human C1q to heart mitochondrial membranes. J Biol Chem 256:10924–10929

    Article  CAS  PubMed  Google Scholar 

  • Sünderhauf A, Raschdorf A, Hicken M, Schlichting H, Fetzer F, Brethack AK, Perner S, Kemper C, Ghebrehiwet B, Sina C, Derer S (2020) GC1qR Cleavage by Caspase-1 Drives Aerobic Glycolysis in Tumor Cells. Front Oncol 10:575854

    Article  PubMed  PubMed Central  Google Scholar 

  • Swerdlow RH, Burns JM, Khan SM (2014) The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochem Biophys Acta 1842:1219–1231

    CAS  PubMed  Google Scholar 

  • Ten VS, Yao J, Ratner V, Sosunov S, Fraser DA, Botto M, Sivasankar B, Morgan BP, Silverstein S, Stark R, Polin R, Vannucci SJ, Pinsky D, Starkov AA (2010) Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury. J Neurosci Offic J Soc Neurosci 30:2077–2087

    Article  CAS  Google Scholar 

  • Tobinick E (2009) Tumour necrosis factor modulation for treatment of Alzheimer’s disease: rationale and current evidence. CNS Drugs 23:713–725

    Article  CAS  PubMed  Google Scholar 

  • Torres AK, Jara C, Park-Kang HS, Polanco CM, Tapia D, Alarcón F, de la Peña A, Llanquinao J, Vargas-Mardones G, Indo JA, Inestrosa NC, Tapia-Rojas C (2021) Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer’s Disease. Journal of Alzheimer’s Disease : JAD 84:1391–1414

    Article  CAS  PubMed  Google Scholar 

  • Tracy TE et al (2022) Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 185:712–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veerhuis R, Van Breemen MJ, Hoozemans JM, Morbin M, Ouladhadj J, Tagliavini F, Eikelenboom P (2003) Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro. Acta Neuropathol 105:135–144

    Article  CAS  PubMed  Google Scholar 

  • Velazquez P, Cribbs DH, Poulos TL, Tenner AJ (1997) Aspartate residue 7 in amyloid beta-protein is critical for classical complement pathway activation: implications for Alzheimer’s disease pathogenesis. Nat Med 3:77–79

    Article  CAS  PubMed  Google Scholar 

  • Wang B, Li Y, Hu S, Peng K (2022) C1q/tumor necrosis factor-related protein 9 protects cultured chondrocytes from IL-1β-induced inflammatory injury by inhibiting NLRP3 inflammasome activation via the AdipoR1/AMPK axis. Environ Toxicol 37:889–898

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Xiong M, Gratuze M, Bao X, Shi Y, Andhey PS, Manis M, Schroeder C, Yin Z, Madore C, Butovsky O, Artyomov M, Ulrich JD, Holtzman DM (2021a) Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron 109:1657–1674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Fu AKY, Ip NY (2021b) IL-33/ST2 Signaling Regulates Synaptic Plasticity and Homeostasis in the Adult Hippocampal Circuitry. DNA Cell Biol 40:1125–1130

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Guo SY, Gu PQ, Wang XM, Sun N, Gao LJ (2014) The globular heads of the C1q receptor regulate apoptosis in human extravillous cytotrophoblast-derived transformed cells via a mitochondria-dependent pathway. Am J Reprod Immunol (New York, NY: 1989) 71:73–85

  • Webster SD, Yang AJ, Margol L, Garzon-Rodriguez W, Glabe CG, Tenner AJ (2000) Complement component C1q modulates the phagocytosis of Abeta by microglia. Exp Neurol 161:127–138

    Article  CAS  PubMed  Google Scholar 

  • Winston CN, Goetzl EJ, Schwartz JB, Elahi FM, Rissman RA (2019) Complement protein levels in plasma astrocyte-derived exosomes are abnormal in conversion from mild cognitive impairment to Alzheimer’s disease dementia. Alzheimer’s & Dementia (amsterdam, Netherlands) 11:61–66

    Article  Google Scholar 

  • Wu J, Bie B, Foss JF, Naguib M (2020a) Amyloid Fibril-Induced Astrocytic Glutamate Transporter Disruption Contributes to Complement C1q-Mediated Microglial Pruning of Glutamatergic Synapses. Mol Neurobiol 57:2290–2300

    Article  CAS  PubMed  Google Scholar 

  • Wu T et al (2019) Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy. Cell Rep 28:2111-2123.e2116

    Article  CAS  PubMed  Google Scholar 

  • Wu XY et al (2020b) Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis. J Autoimmun 106:102336

    Article  PubMed  Google Scholar 

  • Xin YR, Jiang JX, Hu Y, Pan JP, Mi XN, Gao Q, Xiao F, Zhang W, Luo HM (2019) The Immune System Drives Synapse Loss During Lipopolysaccharide-Induced Learning and Memory Impairment in Mice. Front Aging Neurosci 11:279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu D, Zhou X, Chen J, Li N, Ruan S, Zuo A, Lei S, Li L, Guo Y (2022) C1q/tumour necrosis factor-related protein-9 aggravates lipopolysaccharide-induced inflammation via promoting NLRP3 inflammasome activation. Int Immunopharmacol 104:108513

    Article  CAS  PubMed  Google Scholar 

  • Xu N, Li AD, Ji LL, Ye Y, Wang ZY, Tong L (2019) miR-132 regulates the expression of synaptic proteins in APP/PS1 transgenic mice through C1q. Eur J Histochem 63

  • Xu X, Zhang A, Zhu Y, He W, Di W, Fang Y, Shi X (2018) MFG-E8 reverses microglial-induced neurotoxic astrocyte (A1) via NF-κB and PI3K-Akt pathways. J Cell Physiol 234:904–914

    Article  PubMed  Google Scholar 

  • Yang P, Sheng D, Guo Q, Wang P, Xu S, Qian K, Li Y, Cheng Y, Wang L, Lu W, Zhang Q (2020) Neuronal mitochondria-targeted micelles relieving oxidative stress for delayed progression of Alzheimer’s disease. Biomaterials 238:119844

    Article  CAS  PubMed  Google Scholar 

  • Yin C et al (2019) ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med 25:496–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin X, Qiu Y, Zhao C, Zhou Z, Bao J, Qian W (2021) The Role of Amyloid-Beta and Tau in the Early Pathogenesis of Alzheimer’s Disease. Med Sci Moni Int Med J Exp Clin Res 27

    CAS  Google Scholar 

  • Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido Takaomi C, Maeda J, Suhara T, Trojanowski JQ, Lee VMY (2007) Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model. Neuron 53:337–351

    Article  CAS  PubMed  Google Scholar 

  • Zaki Y, Cai DJ (2020) Creating Space for Synaptic Formation-A New Role for Microglia in Synaptic Plasticity. Cell 182:265–267

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Fonseca MI, Pisalyaput K, Tenner AJ (2008) Complement C3 and C4 expression in C1q sufficient and deficient mouse models of Alzheimer’s disease. J Neurochem 106:2080–2092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zotova E, Bharambe V, Cheaveau M, Morgan W, Holmes C, Harris S, Neal JW, Love S, Nicoll JA, Boche D (2013) Inflammatory components in human Alzheimer’s disease and after active amyloid-β42 immunization. Brain J Neurol 136:2677–2696

    Article  Google Scholar 

Download references

Funding

This research was funded by the National Natural Science Foundation of China (CN), grant number 81870840 and the Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern Univeristy, Shenyang, China (2022JH13/10200026).

Author information

Authors and Affiliations

  1. College of Life and Health Sciences, Northeastern University, 110819, Shenyang, People’s Republic of China

    Pei-Pei Guan, Tong-Qi Ge & Pu Wang

Authors
  1. Pei-Pei Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tong-Qi Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pu Wang.

Ethics declarations

Conflict of Interest

The authors declare no competing financial interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, PP., Ge, TQ. & Wang, P. As a Potential Therapeutic Target, C1q Induces Synapse Loss Via Inflammasome-activating Apoptotic and Mitochondria Impairment Mechanisms in Alzheimer’s Disease. J Neuroimmune Pharmacol 18, 267–284 (2023). https://doi.org/10.1007/s11481-023-10076-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-023-10076-9

Keywords

Search

Navigation