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Complementing Tau: New Data Show that the Complement System Is Involved in Degeneration in Tauopathies

2018; Cell Press; Volume: 100; Issue: 6 Linguagem: Inglês

10.1016/j.neuron.2018.12.003

1097-4199

C. T. M. Davies, Tara L. Spires‐Jones,

S100 Proteins and Annexins

Innate immunity is increasingly recognized to contribute to the pathogenesis of neurodegenerative disorders. In this issue of Neuron, Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar and Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar describe mechanisms by which the complement system influences tau-mediated degeneration in mouse models of tauopathy. Innate immunity is increasingly recognized to contribute to the pathogenesis of neurodegenerative disorders. In this issue of Neuron, Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar and Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar describe mechanisms by which the complement system influences tau-mediated degeneration in mouse models of tauopathy. Alzheimer's disease (AD), the most common cause of dementia, affects more than 30 million people worldwide and costs the world's economies more than $500 billion per year. An incomplete understanding of AD pathogenesis has thus far prevented the development of disease-modifying treatments. A potential pathway to synapse and neuron degeneration involves increased activation of the complement cascade, part of the brain's innate immune system. Originally thought to be a secondary outcome to degenerative processes, a growing body of genetic and epidemiological evidence now strongly implicates cells and proteins involved in the innate immune system in modulating the risk of developing AD (De Strooper and Karran, 2016De Strooper B. Karran E. The cellular phase of Alzheimer's disease.Cell. 2016; 164: 603-615Abstract Full Text Full Text PDF PubMed Scopus (945) Google Scholar). During normal brain development, microglia- and astrocyte-mediated synapse pruning is crucial in forming precise synaptic circuits (Stevens et al., 2007Stevens B. Allen N.J. Vazquez L.E. Howell G.R. Christopherson K.S. Nouri N. Micheva K.D. Mehalow A.K. Huberman A.D. Stafford B. et al.The classical complement cascade mediates CNS synapse elimination.Cell. 2007; 131: 1164-1178Abstract Full Text Full Text PDF PubMed Scopus (1972) Google Scholar, Schafer et al., 2012Schafer D.P. Lehrman E.K. Kautzman A.G. Koyama R. Mardinly A.R. Yamasaki R. Ransohoff R.M. Greenberg M.E. Barres B.A. Stevens B. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner.Neuron. 2012; 74: 691-705Abstract Full Text Full Text PDF PubMed Scopus (2244) Google Scholar). This process involves activation of the classical complement system, initiated by deposition of C1q on material to be eliminated. The cascade converges on the central complement component C3, whose fragments interact with their receptors, C3aR and CR3, to enact downstream immune effects such as phagocytosis. In disease, these developmental mechanisms might be reactivated, with glial engulfment of synapses contributing to synapse loss and disease progression. In AD patient brains, the pathological proteins amyloid-β (Aβ) and tau are thought to contribute to the synapse and neuron loss that causes dementia symptoms (Spires-Jones and Hyman, 2014Spires-Jones T.L. Hyman B.T. The intersection of amyloid beta and tau at synapses in Alzheimer's disease.Neuron. 2014; 82: 756-771Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar). Several papers now link Aβ-mediated synapse loss to the complement system in mouse models of AD. In plaque-bearing mouse models, C1q decorates post-synaptic densities that are then thought to be cleared by microglia through activation of CR3 (Hong et al., 2016Hong S. Beja-Glasser V.F. Nfonoyim B.M. Frouin A. Li S. Ramakrishnan S. Merry K.M. Shi Q. Rosenthal A. Barres B.A. et al.Complement and microglia mediate early synapse loss in Alzheimer mouse models.Science. 2016; 352: 712-716Crossref PubMed Scopus (1530) Google Scholar). Although the complement pathway has been suggested to play an active role in tau pathology and tau-mediated synapse loss (Britschgi et al., 2012Britschgi M. Takeda-Uchimura Y. Rockenstein E. Johns H. Masliah E. Wyss-Coray T. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice.J. Neuroinflammation. 2012; 9: 220Crossref PubMed Scopus (28) Google Scholar), the mechanisms remain unknown. In this issue of Neuron, Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar and Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar provide mechanistic data linking tau pathology and the complement system. Both studies examined human brain tissue from AD and tauopathy patients, as well as the PS19 mouse model of tauopathy, in which animals express human tau containing the P301S frontotemporal dementia-associated mutation. In the human AD brain, Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar found C1q and pathological tau proteins to be increased and enriched at post-synapses. Consistent with these proteins associating with one another, C1q levels positively correlated with the levels of pathological tau. Using RNA sequencing (RNA-seq) data from human AD patients, Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar show that increased expression of the downstream complement components C3 and C3aR1 was associated with worsened cognitive function and with the degree of tau pathology. Additionally, in the brains of patients with other tauopathies that lack Aβ pathology, C3 and C3aR1 expression was also increased, supporting a role for complement components in human tauopathy. To probe how the complement system might influence tau-mediated synapse loss, Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar utilized the PS19 tauopathy mouse model at an age when they are in the early stages of disease progression, before they exhibit overt neuronal loss in their hands. Proteomics of post-synapses in these mice revealed C1q to be one of the most highly upregulated proteins. The amount of C1q present was positively correlated with the amount of pathological tau, like in the human AD brain. Temporally, the increase in synaptic C1q lagged slightly behind increases in pathological tau, consistent with tau inducing C1q accumulation at the synapse. Interestingly, C1q and human tau preferentially associated with one another at excitatory synapses, while inhibitory post-synapses were largely spared. C1q accumulation at post-synapses was also higher in the tauopathy mice than in a model of Aβ pathology, suggesting that pathological tau is particularly potent in activating the complement system. C1q-tagged synapses are thought to be engulfed by microglia, potentially contributing to synapse loss. In line with this, tau transgenic mice had reduced synapse density, and microglia in these animals had increased levels of synaptic markers within lysosomes. Thus, pathological tau likely induces C1q accumulation at synapses, tagging them for removal by microglial phagocytosis. Notably, neutralization of C1q in tau transgenic mice, via intracerebral injection of an anti-C1q antibody, reduced microglial engulfment of synaptic components and led to a small but significant rescue of synapse density 5 days after injection, highlighting the translational potential of these results. In addition to the C1q effects, proteomics in tau transgenic mice also revealed the downregulation of a group of proteins that are involved in the regulation of Rho GTPases, which control actin dynamics and have previously been implicated as critical components in AD pathogenesis (Bolognin et al., 2014Bolognin S. Lorenzetto E. Diana G. Buffelli M. The potential role of rho GTPases in Alzheimer's disease pathogenesis.Mol. Neurobiol. 2014; 50: 406-422Crossref PubMed Scopus (25) Google Scholar). Experimental depletion of these proteins in vitro resulted in reduced spine density that could be rescued by pharmacological stabilization of actin. Thus, tau pathology may downregulate these proteins and lead to altered actin dynamics and subsequent spine loss, highlighting a molecular mechanism by which tau pathology may directly mediate synapse loss without the need for microglial engulfment. The paper by Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar in this issue further supports a role for the complement system in the development of tau pathology, tau-mediated synapse degeneration, and neuron loss. Following on from their finding that central complement components are increased in human tauopathies, Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar examine how signaling by C3-C3aR modulates tau pathology by crossing PS19 mice with mice deficient in C3aR1, the gene for C3aR. Tau transgenic mice developed tau pathology, neuroinflammation, synapse and neuronal loss, and impairments of neuronal plasticity and cognition by 9 months of age in this study. Quite remarkably, upon knockout of C3aR1, somatodendritic accumulation of tau was almost completely ameliorated. This was accompanied by a curtailing of neuroinflammation, rescue of synapse and neuronal loss, and improvements in neuronal function. Transcriptomics of bulk tissue and specific cell types (microglia and astrocytes) revealed a host of genes related to immune pathways to be upregulated in tau transgenic mice. Strikingly, deletion of C3aR1 normalized transcription of these immune-related genes and reversed gene signatures typical of disease-associated microglia and neurotoxic astrocytes, which have been implicated in neurodegeneration, indicative of C3-C3aR signaling regulating these changes and mediating immune homeostasis in the context of tau pathology. Considering that deletion of C3aR1 had such widespread effects on many genes, Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar postulated that C3aR may regulate transcription factors, particularly within microglia. Indeed, they identify the transcription factor STAT3 as a novel direct target and downstream effector of C3aR. Upon activation, the STAT family of transcription factors become phosphorylated and translocate to the nucleus, where they mediate target gene transcription. Inhibition of STAT3 phosphorylation with a pharmacological compound was able to reduce tau pathology and neuroinflammation, although to a slightly lesser degree than C3aR1 knockout, providing novel insights into this pathway that may be amenable to therapeutic intervention. Both studies highlight a role for the complement system in modulating tau pathology and tau-mediated synapse loss. Taking these two studies together, one might hypothesize that, regarding tau pathology, the complement system contributes to a "double-hit" mechanism, perpetuating a cycle of exacerbated tau pathology and tau-mediated synapse loss (Figure 1). In such a cycle, enhanced activation of C3-C3aR signaling, potentially acting through STAT3, exacerbates tau pathology and neuroinflammation. Exacerbated tau pathology results in increased C1q tagging of synapses and subsequent synapse loss by microglial engulfment. Activation of the classical complement pathway via C1q leads to increased activation of C3 and increased signaling through C3aR, thereby perpetuating the cycle and exacerbating tau pathology and synapse loss, eventually leading to the gross neuronal loss and atrophy seen in AD. Although outstanding in many ways, the current studies do have limitations. These include using a single mutant tau overexpressing transgenic model for mechanistic studies. One limitation of this model is apparent in the differing phenotypes observed at the same age between these two studies. Neuron loss was not observed by one group and was observed and modulated by knockout of C3aR1 by the other. Additionally, the human tau mutation in these transgenic models is associated with frontotemporal dementia and so may not be entirely representative of other tauopathies, such as AD. It will be valuable to repeat these studies in other tau mouse models, including knockin lines, and to further test whether modulating the complement system can prevent or reverse synapse dysfunction, synapse loss, and neuronal loss. Nonetheless, it is encouraging that in both papers, the authors include human tissue and/or datasets and report complementary findings to those in their mouse models, suggesting that these data might be translationally relevant. Some key questions for future work remain. It is still not clear whether microglia phagocytose "live" synapses or simply clear debris left by injured neurons. Although Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar suggest that, at least in vitro, microglia remove intact synapses, this requires further investigation. It will also be imperative to determine whether this occurs in human brain. It is interesting that Dejanovic et al., 2018Dejanovic B. Huntley M.A. De Mazière A. Meilandt W.J. Wu T. Srinivasan K. Jiang Z. Gandham V. Friedman B.A. Ngu H. et al.Changes in the synaptic proteome in tauopathy and rescue of tau-induced synapse loss by C1q antibodies.Neuron. 2018; 100 (this issue): 1322-1336Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar find inhibitory synapses to be largely protected from C1q tagging and subsequent microglial engulfment. Imbalance of excitatory and inhibitory connections in the brain has repeatedly been implicated in many neurodegenerative diseases, and hopefully, future work will determine why there appears to be a preference for complement-mediated removal of excitatory synapses and how this impacts upon network function. Identification of synaptic receptors for C1q will be important and may help shed light on how synapses are selected for elimination while also revealing targets more amenable to therapeutic intervention. In regard to Litvinchuk et al., 2018Litvinchuk A. Wan Y.-W. Swartzlander D.B. Chen F. Cole A. Propson N.E. Wang Q. Zhang B. Liu Z. Zheng H. Complement c3ar inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and alzheimer's disease.Neuron. 2018; 100 (this issue): 1337-1353Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, an investigation into how C3-C3aR signaling influences the neuronal transcriptome might also reveal more mechanistic insight into how this pathway modulates tau pathology. Both studies support a role of the complement system in tauopathy and tau-mediated synapse degeneration and highlight avenues for potential therapeutic intervention that warrant further investigation. This adds to a growing, dare we say "inflamed," excitement in the field surrounding the crosstalk between multiple cell types in neurodegeneration. C.D. is a student on the Wellcome Trust Translational Neuroscience PhD Programme at the University of Edinburgh (grant 203972/Z/16/Z). T.S.J. is funded by the University of Edinburgh, UK Dementia Research Institute, and European Research Council (ALZSYN). We gratefully acknowledge membership in Edinburgh Neuroscience. T.S.J. is a member of the Scientific Advisory Board of Cognition Therapeutics. The company did not fund or have any influence over this paper. Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q AntibodiesDejanovic et al.NeuronNovember 1, 2018In BriefUnbiased proteomics reveals multiple molecular changes at hippocampal synapses that occur prior to neurodegeneration in a taupathy/Alzheimer's disease mouse model. Complement C1q labels phospho-Tau-containing synapses and drives microglia-mediated synapse loss that can be rescued by a C1q-blocking antibody. Full-Text PDF Open ArchiveComplement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer's DiseaseLitvinchuk et al.NeuronNovember 8, 2018In BriefLitvinchuk et al. show that complement C3aR plays a critical role in mediating immune homeostasis and tau pathology. The identification of a conserved C3aR network and crosstalk between complement signaling with STAT3 activation reveal novel pathogenic and therapeutic insights. Full-Text PDF Open Archive