Getting Too Old Too Quickly for Their Job: Senescent Glial Cells Promote Neurodegeneration
Authors: David Gosselin, Serge Rivest
Journal: Neuron (2018)

In a provocative study recently published in Nature, Bussian et al., 2018Bussian T.J. Aziz A. Meyer C.F. Swenson B.L. van Deursen J.M. Baker D.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline.Nature. 2018; 562: 578-582Crossref PubMed Scopus (534) Google Scholar report that in tauopathies, glial cells, but not neurons, may be prone to enter cell senescence. Importantly, eliminating senescent glial cells preserves neuronal functions and prevents cognitive decline. In a provocative study recently published in Nature, Bussian et al., 2018Bussian T.J. Aziz A. Meyer C.F. Swenson B.L. van Deursen J.M. Baker D.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline.Nature. 2018; 562: 578-582Crossref PubMed Scopus (534) Google Scholar report that in tauopathies, glial cells, but not neurons, may be prone to enter cell senescence. Importantly, eliminating senescent glial cells preserves neuronal functions and prevents cognitive decline. In cell biology, senescence is a cellular state primarily characterized by irreversible cell-cycle arrest, extensive changes in gene expression, and the secretion of a range of mediators of inflammation, including cytokines, chemokines, and proteases. Senescent cells also express high levels of cell-cycle inhibitory protein p16INK4A and display enhanced β-galactosidase activity (β-Gal). These latter features are significant as they can be used as biomarkers to reveal the presence of senescent cells in tissues. Multiple factors can contribute to a cell entering senescence, including DNA damage, telomere shortening, oncogenic mutations, metabolic and mitochondrial dysfunctions, and inflammation. Notably, senescent cells do not readily undergo apoptosis. Indeed, evidence suggests that presence of senescent cells within a physiological range may actually help suppress tumorigenesis while also promoting tissue repair mechanisms (Campisi, 2013Campisi J. Aging, cellular senescence, and cancer.Annu. Rev. Physiol. 2013; 75: 685-705Crossref PubMed Scopus (1651) Google Scholar). Thus, senescent cells participate in maintenance of organ homeostasis and functions. However, in aging, senescent cells accumulate significantly, and this overabundance appears to contribute to tissue lesions and dysfunctions associated with aging (van Deursen, 2014van Deursen J.M. The role of senescent cells in ageing.Nature. 2014; 509: 439-446Crossref PubMed Scopus (1428) Google Scholar). Although the presence of senescent cells has been reported in cases of brain diseases (Baker and Petersen, 2018Baker D.J. Petersen R.C. Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives.J. Clin. Invest. 2018; 128: 1208-1216Crossref PubMed Scopus (200) Google Scholar), our knowledge of their roles in brain diseases associated with aging remains limited. To address this critical problem, Bussian et al. conducted a series of studies to reveal and characterize senescent cells in the PS19 mouse model of frontotemporal dementia associated with tau hyperphosphorylation (Bussian et al., 2018Bussian T.J. Aziz A. Meyer C.F. Swenson B.L. van Deursen J.M. Baker D.J. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline.Nature. 2018; 562: 578-582Crossref PubMed Scopus (534) Google Scholar) and development of neurofibrillary tangles. First, compared to age-matched controls, the authors observed higher mRNA expression of the gene coding for p16INK4A, Cdkna2, in cortical and hippocampal areas of PS19 mice, starting at 4 months of age. Notably, the Cdkna2 mRNA elevation in PS19 mice occurs before cognitive impairments arise in these mice, which typically occurs around 6 months of age (Takeuchi et al., 2011Takeuchi H. Iba M. Inoue H. Higuchi M. Takao K. Tsukita K. Karatsu Y. Iwamoto Y. Miyakawa T. Suhara T. et al.P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating.PLoS ONE. 2011; 6: e21050Crossref PubMed Scopus (113) Google Scholar). Intriguingly, qPCR analyses performed on purified brain cell populations isolated by flow cytometry revealed that astrocytes and microglia, but not neurons or oligodendrocytes, are the cells responsible for the increase in Cdkna2 mRNA expression in PS19 mice. Therefore, these results strongly suggest that senescent astrocytes and microglia accumulate in the brain in a context of tau-associated pathologies. Importantly, the authors confirmed this observation independently by β-Gal staining visualization in electron microscopy. As glial cells, astrocytes and microglia are essential support cells to ensure proper functioning of the brain. However, in a state of senescence, these cells could possibly fail to execute properly their neuronal-nursing functions and/or acquire neurotoxic properties. Thus, accumulation of senescent glia in the brain prior to cognitive decline in PS19 mice is significant because it suggests the hypothesis that these cells may directly contribute to learning and memory problems that arise in these mice. To test this, Bussian and colleagues devised two distinct genetically and pharmacologically based strategies to prevent senescent cells from accumulating in the brain. First, they leveraged a robust transgenic mouse model, the p16INK4A-ATTAC mouse line, to eliminate senescent cells as they emerge in PS19 mice (Baker et al., 2011Baker D.J. Wijshake T. Tchkonia T. LeBrasseur N.K. Childs B.G. van de Sluis B. Kirkland J.L. van Deursen J.M. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.Nature. 2011; 479: 232-236Crossref PubMed Scopus (2162) Google Scholar). The p16INK4A-ATTAC transgenic mouse codes for a FK506 binding protein fused to caspase 8, and mRNA expression of the construct is driven by the promoter sequence of p16INK4A (i.e., Cdkna2). In the presence of FK506 ligand AP20187, the fusion protein becomes functional and triggers cell apoptosis specifically in p16INK4A-expressing cells. Importantly, Bussian and colleagues found that AP20187 treatment of PS19-p16INK4A-ATTAC transgenic mice effectively prevented appearance of senescent glial cells and that this led to a significant reduction of the presence of tau aggregates in neurons. Of note, these effects translated into highly beneficial outcomes for brain tissue integrity and functions. Indeed, elimination of senescent cells prevented neuronal loss in the dentate gyrus and overall brain atrophy, as well as cognitive decline in an object-recognition task. In a second series of experiments, Bussian et al. tested the ability of senolytic compound ABT263 to limit accumulation of tau in the brain of PS19 mice. Treating mice prophylactically with ABT263 before senescent glial cells appeared prevented their accumulation and the formation of tau aggregates in neurons. Although no behavioral results were provided to assess effects on brain functions, these data nonetheless suggest that pharmacological approaches may provide therapeutic benefits in tauopathies. Overall, the study by Bussian et al. provides key evidence indicating that accumulation of senescent glial cells may be a core component of disease mechanisms in neurodegeneration, a concept that had received little attention before. Furthermore, the demonstration that senolytic treatments may reverse disease course is significant, especially in light of the increasing interests in pharmacological chemistry to design an efficient senolytic compound for various diseases associated with aging. However, there remain numerous key questions pertaining to the underlying molecular biology of glial cell senescence and the extent to which other neurodegenerative diseases also depend on the activity of these cells. Interestingly, another study recently reported evidence corroborating a pathological role of cell senescence in promoting tau-dependent neurodegeneration (Musi et al., 2018Musi N. Valentine J.M. Sickora K.R. Baeuerle E. Thompson C.S. Shen Q. Orr M.E. Tau protein aggregation is associated with cellular senescence in the brain.Aging Cell. 2018; (Published online August 20, 2018)https://doi.org/10.1111/acel.12840Crossref PubMed Scopus (241) Google Scholar). Using the rTg4510 mouse model of tau-associated frontotemporal dementia, Musi and colleagues detected enhanced brain expression of Cdkna2 mRNA at the onset of appearance of neurofibrillary tangles compared to age-matched controls. Furthermore, treating these mice with senolytic drugs inhibited development of tangles. Importantly, the authors were able to validate that neurons that have neurofibrillary tangles in patients with Alzheimer’s disease (AD) also display high expression of Cdkna2 mRNA senescent marker. Although the authors did not report data on glial senescence, this study nevertheless provides critical independent support for the hypothesis that senescence of brain cells actively promotes neurodegeneration. Notably, however, the study by Musi et al. suggested that senescence as an effector mechanism of neurodegeneration may not be a mechanism common to all neurodegenerative diseases. Indeed, whereas Cdkna2 mRNA became elevated in the mouse model of tauopathy, they were not detected in 3xTG mice that develop amyloid beta (Aβ)-related lesions. The observation that senescence is associated with tauopathies, but not Aβ-dependent lesions, offers some tentative insights into the biology of senescent glial cells. First, it suggests that pathological accumulation of Aβ may be neither necessary nor sufficient to trigger neurotoxic glial senescence. Also, because accumulation of Aβ peptides in the brain extracellular space triggers persistent microglial activation and inflammation, data from the study by Musi and colleagues suggest that chronic inflammation does not invariably trigger glial senescence. We note that microglia have the ability to clear Aβ peptides from the brain, and such a natural innate immune mechanism has been shown to be highly beneficial in mouse models of AD (Rivest, 2009Rivest S. Regulation of innate immune responses in the brain.Nat. Rev. Immunol. 2009; 9: 429-439Crossref PubMed Scopus (651) Google Scholar). In this context, induction of microglial senescence by Aβ peptides would indeed be counterproductive in that regard. Therefore, it seems that for dementias, a key role for glial senescence may be restricted to cases involving certain types of tauopathies. In light of these observations, it will be essential to identify the mechanism by which tau promotes pathological accumulation of senescent glial cells. Intriguingly, we note that a previous study in PS19 mice reported that microglia are involved in neuronal tau internalization and the spreading of its hyperphosphorylated form (Asai et al., 2015Asai H. Ikezu S. Tsunoda S. Medalla M. Luebke J. Haydar T. Wolozin B. Butovsky O. Kügler S. Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation.Nat. Neurosci. 2015; 18: 1584-1593Crossref PubMed Scopus (872) Google Scholar). This is significant because it indicates that microglia can directly interact with hyperphosphorylated tau of neuronal origin. Given this, one could propose the hypothesis that internalization of hyperphosphorylated tau by microglia disrupts their cell homeostasis and triggers senescence (Figure 1). Another point of interest for future studies will be the identification of the respective contribution of microglial and astrocytic cell senescence to tauopathies. We note that data from the Bussian et al. study indicate higher fold induction of p16INK4A in astrocytes compared to microglia, suggesting that these cells may display higher sensitivity for entering senescence. Furthermore, work from the late Ben Barres suggests that astrocytes can acquire a highly neurotoxic phenotype in diseases, i.e., A1 astrocytes (Liddelow et al., 2017Liddelow S.A. Guttenplan K.A. Clarke L.E. Bennett F.C. Bohlen C.J. Schirmer L. Bennett M.L. Münch A.E. Chung W.S. Peterson T.C. et al.Neurotoxic reactive astrocytes are induced by activated microglia.Nature. 2017; 541: 481-487Crossref PubMed Scopus (3349) Google Scholar). The extent to which senescent astrocytes relate to the A1 phenotype, or represent an entirely distinct subset of astrocytes, remains to be seen. Our understanding of the mechanisms that underlie neurodegenerative diseases remains limited and this greatly impedes our ability to develop effective therapies to treat them. Without a doubt, new concepts supported by robust studies are required to move forward with qualitatively novel approaches to treat neurodegenerative diseases. To this end, the study by Bussian et al. offers exciting ideas that will hopefully bring us closer to effective disease-modifying therapies that will prevent, stop, and/or even reverse the course of neurodegenerative disorders. D.G. is supported by Fonds de Recherche du Québec – Santé, Fondation du CHU de Québec, and Fondation Hélène Hallé. S.R. holds a CIHR Canadian Research Chair in Neuroimmunology.