- Email: [email protected]
Microglia Metabolic Breakdown Drives Alzheimer’s Pathology
Cell Metabolism
Previews Microglia Metabolic Breakdown Drives Alzheimer’s Pathology F. Chris Bennett1,* and Shane A. Liddelow2,3,* 1Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and the Children’s Hospital of Philadelphia, Philadelphia, PA, USA 2Neuroscience Institute, NYU School of Medicine, New York, NY, USA 3Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA *Correspondence: [email protected] (F.C.B.), [email protected] (S.A.L.) https://doi.org/10.1016/j.cmet.2019.08.017
Altered metabolic function is common in stressed immune cells, but alteration in brain microglia during neurodegeneration is not understood. In this issue, Baik et al. (2019) provide insight into microglial metabolism. They demonstrate a switch from oxidative phosphorylation to glycolysis following interaction with amyloid beta acutely, and breakdown in both pathways chronically. Alzheimer’s disease (AD) is a debilitating neurodegenerative disease affecting tens of millions of people worldwide. There are currently no effective therapeutics to prevent or slow its progression. The neuropathology of AD is well described and characterized by accumulation of two pathogenic protein aggregates: neurofibrillary tangles, made of tau protein, and senile plaques, made of amyloid beta (Ab) fragments. These aggregates are associated with neuronal loss, but recent therapies targeting Ab plaques have been unsuccessful. This is likely because AD is a chronic disease that unfolds over decades, with a complex physiology of which Ab accumulation is one component. Glia, the largest cellular component of the brain, comprising several non-neuronal cells, have emerged as key players in AD pathogenesis. For example, dysfunctional activation of astrocytes in mouse models of AD have been shown to cause neuronal death (Shi et al., 2017), likely mediated by activation of microglia, the brain’s resident macrophages (Li and Barres, 2018). In fact, many genes increasing risk for AD are expressed specifically in microglia (Sims et al., 2017). Mutations in TREM2 (hTREM2), a microglia phagocytic receptor, are implicated in early onset AD in humans, but the mechanistic roles of TREM2 in AD remain largely unknown. In mouse models, it is required for microglia to adopt an AD-associated transcriptomic signature that some studies suggest exacerbates neuronal loss. But what induces pathological microglia in AD? Metabolism has emerged as a key regulator of the innate immune system
(Pollizzi and Powell, 2014) but has received less attention in the context of neurodegenerative diseases. In 2017, Colonna and colleagues proposed that TREM2 signaling potentiated microglial responses in AD by sustaining ATP production (Ulland et al., 2017)—suggesting a strong correlation between microgliaspecific AD risk alleles and metabolic function. But what causes the reduced ATP production ultimately mitigated by TREM2? This month, Baik and colleagues (Baik et al., 2019) present exciting new results showing Ab modification of microglial metabolism. This intriguing study starts by investigating a well-known microglial function: phagocytosis. Taking advantage of reductionist cell culture approaches, the authors show that while microglia are able to phagocytose debris in a physiological setting, addition of Ab was sufficient to increase their phagocytic capacity. In addition, Ab treatment pushed these cells into a disease reactive state characterized by increased secretion of the inflammatory cytokines IL-1b, IL-10, and TNFa. These data suggest that Ab may act as a ‘‘danger signal’’ for microglia. As previous studies have shown that functional changes in peripheral immune cells can be mediated by their metabolic function, the authors next investigated possible roles of Ab in altering microglial metabolism. In vitro, Ab alone was sufficient to rapidly switch microglia metabolism from respiratory to glycolytic. This glycolytic switch was required for pro-inflammatory state change in microglia as it was blocked by inhibition of
glycolysis (Figure 1). But what pathways are involved in mediating this process? To investigate this, Baik et al. pharmacologically inhibited mTOR signaling, a major regulator of glucose metabolism. They found it decreases release of IL-1b and TNFa, implicating mTOR signaling in Ab-induced microglial metabolic shift. As AD is a chronic neurodegenerative disease, the authors next decided to investigate changes in microglial function following chronic Ab exposure. While a single 24 h treatment with Ab drove a pro-inflammatory state change in microglia, chronic treatment did not. Similarly, while acute Ab was paired with an increase in phagocytic capacity, chronic Ab dramatically decreased phagocytic activity by microglia (Figure 1). These experiments highlight that Ab can have different functional and metabolic effects on a single cell in different settings—acute and chronic. Microglia undergo dramatic transcriptional and functional changes when removed from the brain, including dramatic increases in phagocytosis when cultured in serum (Bohlen et al., 2017), making it critical to validate these conclusions in vivo. Using aged 5XFAD transgenic mice as an in vivo model of chronic Ab exposure, the authors show microglia with chronic amyloid burden are less transcriptionally reactive to an injection of Ab than wild-type (WT) controls, suggesting WT microglia are more metabolically and immunologically responsive. Next, the authors investigated microglial responses to acute injury in vivo by imaging process extension. Following laserablation injury (Davalos et al., 2005),
Cell Metabolism 30, September 3, 2019 ª 2019 Elsevier Inc. 405
Cell Metabolism
Previews
Figure 1. Microglial Metabolism, Phagocytosis, and Cytokine Secretion Are Altered Following Interaction with Amyloid Beta Acute interaction drives glycolysis and cytokine release, and enhances phagocytic activity. Chronic interaction with amyloid reverses this response, driving down cytokine release and phagocytosis and keeping overall metabolic function low. Figure created with BioRender.
microglial process extension toward the injury site was decreased in 5XFAD mice compared to WT controls. These data suggest that chronic exposure of Ab to microglia in 5XFAD mice is sufficient to decrease their responses to additional acute noxious stimuli. But can these apparent disease-associated changes in microglia function and metabolism be reverted? In a final set of experiments, the authors used a metabolism-boosting approach to revert loss of normal microglial function seen in chronic Ab treatment. Treating isolated microglia in culture with IFN-g (to drive mTOR signaling and reverse mTOR-dependent loss-of-function effects), the cells responded with a boost in glycolytic metabolic function. IFN-g-treated microglia also regained some normal functions, namely enhanced pro-inflammatory responses and return of phagocytic activity. They also found chronic (3 month) infusion of IFN-g into 5XFAD mice was paired with greater recruitment of microglia to amyloid plaques, greater phagocytosis of plaques upon arrival, and greater numbers of CD68+ phagolysosomes in microglia associated with plaques. This study highlights a major difference in acute and chronic interactions of microglia with Ab. While pro-inflammatory re406 Cell Metabolism 30, September 3, 2019
sponses dominate in the acute setting, a loss of responsive ability dominates more chronically. Here Baik et al. provide key new insights into cellular interactions and functional changes that occur in diseases like AD. But they also bring exciting additional key questions to light. Does Tau have a similar effect on microglial metabolism/function as Ab, and what about pathogenic proteins in other neurodegenerative diseases (e.g., alpha synuclein, TDP-43)? Does this position Ab as an initiator of disease, and microglia as a responder—rather than the reverse, which appears true from several other recent studies that implicate microgliaspecific gene mutations as drivers of disease? And what of sexual dimorphisms in the microglial loss of functions reported here? These and many more questions will no doubt be answered in the next few years; the fact remains, however, that modulation of microglial bioenergetics pathways represents a new avenue for possible treatment in diseases like AD.
Bohlen, C.J., Bennett, F.C., Tucker, A.F., Collins, H.Y., Mulinyawe, S.B., and Barres, B.A. (2017). Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e8. Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S., Littman, D.R., Dustin, M.L., and Gan, W.B. (2005). ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758. Li, Q., and Barres, B.A. (2018). Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242. Pollizzi, K.N., and Powell, J.D. (2014). Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14, 435–446. Shi, Y., Yamada, K., Liddelow, S.A., Smith, S.T., Zhao, L., Luo, W., Tsai, R.M., Spina, S., Grinberg, L.T., Rojas, J.C., et al.; Alzheimer’s Disease Neuroimaging Initiative (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527.
REFERENCES
Sims, R., van der Lee, S.J., Naj, A.C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B.W., Boland, A., Raybould, R., Bis, J.C., et al.; ARUK Consortium; GERAD/PERADES, CHARGE, ADGC, EADI (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384.
Baik, S.H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.I., and Mook-Jung, I. (2019). A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 30, this issue, 493–507.
Ulland, T.K., Song, W.M., Huang, S.C., Ulrich, J.D., Sergushichev, A., Beatty, W.L., Loboda, A.A., Zhou, Y., Cairns, N.J., Kambal, A., et al. (2017). TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e13.
Previews Microglia Metabolic Breakdown Drives Alzheimer’s Pathology F. Chris Bennett1,* and Shane A. Liddelow2,3,* 1Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and the Children’s Hospital of Philadelphia, Philadelphia, PA, USA 2Neuroscience Institute, NYU School of Medicine, New York, NY, USA 3Department of Neuroscience and Physiology, NYU School of Medicine, New York, NY, USA *Correspondence: [email protected] (F.C.B.), [email protected] (S.A.L.) https://doi.org/10.1016/j.cmet.2019.08.017
Altered metabolic function is common in stressed immune cells, but alteration in brain microglia during neurodegeneration is not understood. In this issue, Baik et al. (2019) provide insight into microglial metabolism. They demonstrate a switch from oxidative phosphorylation to glycolysis following interaction with amyloid beta acutely, and breakdown in both pathways chronically. Alzheimer’s disease (AD) is a debilitating neurodegenerative disease affecting tens of millions of people worldwide. There are currently no effective therapeutics to prevent or slow its progression. The neuropathology of AD is well described and characterized by accumulation of two pathogenic protein aggregates: neurofibrillary tangles, made of tau protein, and senile plaques, made of amyloid beta (Ab) fragments. These aggregates are associated with neuronal loss, but recent therapies targeting Ab plaques have been unsuccessful. This is likely because AD is a chronic disease that unfolds over decades, with a complex physiology of which Ab accumulation is one component. Glia, the largest cellular component of the brain, comprising several non-neuronal cells, have emerged as key players in AD pathogenesis. For example, dysfunctional activation of astrocytes in mouse models of AD have been shown to cause neuronal death (Shi et al., 2017), likely mediated by activation of microglia, the brain’s resident macrophages (Li and Barres, 2018). In fact, many genes increasing risk for AD are expressed specifically in microglia (Sims et al., 2017). Mutations in TREM2 (hTREM2), a microglia phagocytic receptor, are implicated in early onset AD in humans, but the mechanistic roles of TREM2 in AD remain largely unknown. In mouse models, it is required for microglia to adopt an AD-associated transcriptomic signature that some studies suggest exacerbates neuronal loss. But what induces pathological microglia in AD? Metabolism has emerged as a key regulator of the innate immune system
(Pollizzi and Powell, 2014) but has received less attention in the context of neurodegenerative diseases. In 2017, Colonna and colleagues proposed that TREM2 signaling potentiated microglial responses in AD by sustaining ATP production (Ulland et al., 2017)—suggesting a strong correlation between microgliaspecific AD risk alleles and metabolic function. But what causes the reduced ATP production ultimately mitigated by TREM2? This month, Baik and colleagues (Baik et al., 2019) present exciting new results showing Ab modification of microglial metabolism. This intriguing study starts by investigating a well-known microglial function: phagocytosis. Taking advantage of reductionist cell culture approaches, the authors show that while microglia are able to phagocytose debris in a physiological setting, addition of Ab was sufficient to increase their phagocytic capacity. In addition, Ab treatment pushed these cells into a disease reactive state characterized by increased secretion of the inflammatory cytokines IL-1b, IL-10, and TNFa. These data suggest that Ab may act as a ‘‘danger signal’’ for microglia. As previous studies have shown that functional changes in peripheral immune cells can be mediated by their metabolic function, the authors next investigated possible roles of Ab in altering microglial metabolism. In vitro, Ab alone was sufficient to rapidly switch microglia metabolism from respiratory to glycolytic. This glycolytic switch was required for pro-inflammatory state change in microglia as it was blocked by inhibition of
glycolysis (Figure 1). But what pathways are involved in mediating this process? To investigate this, Baik et al. pharmacologically inhibited mTOR signaling, a major regulator of glucose metabolism. They found it decreases release of IL-1b and TNFa, implicating mTOR signaling in Ab-induced microglial metabolic shift. As AD is a chronic neurodegenerative disease, the authors next decided to investigate changes in microglial function following chronic Ab exposure. While a single 24 h treatment with Ab drove a pro-inflammatory state change in microglia, chronic treatment did not. Similarly, while acute Ab was paired with an increase in phagocytic capacity, chronic Ab dramatically decreased phagocytic activity by microglia (Figure 1). These experiments highlight that Ab can have different functional and metabolic effects on a single cell in different settings—acute and chronic. Microglia undergo dramatic transcriptional and functional changes when removed from the brain, including dramatic increases in phagocytosis when cultured in serum (Bohlen et al., 2017), making it critical to validate these conclusions in vivo. Using aged 5XFAD transgenic mice as an in vivo model of chronic Ab exposure, the authors show microglia with chronic amyloid burden are less transcriptionally reactive to an injection of Ab than wild-type (WT) controls, suggesting WT microglia are more metabolically and immunologically responsive. Next, the authors investigated microglial responses to acute injury in vivo by imaging process extension. Following laserablation injury (Davalos et al., 2005),
Cell Metabolism 30, September 3, 2019 ª 2019 Elsevier Inc. 405
Cell Metabolism
Previews
Figure 1. Microglial Metabolism, Phagocytosis, and Cytokine Secretion Are Altered Following Interaction with Amyloid Beta Acute interaction drives glycolysis and cytokine release, and enhances phagocytic activity. Chronic interaction with amyloid reverses this response, driving down cytokine release and phagocytosis and keeping overall metabolic function low. Figure created with BioRender.
microglial process extension toward the injury site was decreased in 5XFAD mice compared to WT controls. These data suggest that chronic exposure of Ab to microglia in 5XFAD mice is sufficient to decrease their responses to additional acute noxious stimuli. But can these apparent disease-associated changes in microglia function and metabolism be reverted? In a final set of experiments, the authors used a metabolism-boosting approach to revert loss of normal microglial function seen in chronic Ab treatment. Treating isolated microglia in culture with IFN-g (to drive mTOR signaling and reverse mTOR-dependent loss-of-function effects), the cells responded with a boost in glycolytic metabolic function. IFN-g-treated microglia also regained some normal functions, namely enhanced pro-inflammatory responses and return of phagocytic activity. They also found chronic (3 month) infusion of IFN-g into 5XFAD mice was paired with greater recruitment of microglia to amyloid plaques, greater phagocytosis of plaques upon arrival, and greater numbers of CD68+ phagolysosomes in microglia associated with plaques. This study highlights a major difference in acute and chronic interactions of microglia with Ab. While pro-inflammatory re406 Cell Metabolism 30, September 3, 2019
sponses dominate in the acute setting, a loss of responsive ability dominates more chronically. Here Baik et al. provide key new insights into cellular interactions and functional changes that occur in diseases like AD. But they also bring exciting additional key questions to light. Does Tau have a similar effect on microglial metabolism/function as Ab, and what about pathogenic proteins in other neurodegenerative diseases (e.g., alpha synuclein, TDP-43)? Does this position Ab as an initiator of disease, and microglia as a responder—rather than the reverse, which appears true from several other recent studies that implicate microgliaspecific gene mutations as drivers of disease? And what of sexual dimorphisms in the microglial loss of functions reported here? These and many more questions will no doubt be answered in the next few years; the fact remains, however, that modulation of microglial bioenergetics pathways represents a new avenue for possible treatment in diseases like AD.
Bohlen, C.J., Bennett, F.C., Tucker, A.F., Collins, H.Y., Mulinyawe, S.B., and Barres, B.A. (2017). Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e8. Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S., Littman, D.R., Dustin, M.L., and Gan, W.B. (2005). ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758. Li, Q., and Barres, B.A. (2018). Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242. Pollizzi, K.N., and Powell, J.D. (2014). Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14, 435–446. Shi, Y., Yamada, K., Liddelow, S.A., Smith, S.T., Zhao, L., Luo, W., Tsai, R.M., Spina, S., Grinberg, L.T., Rojas, J.C., et al.; Alzheimer’s Disease Neuroimaging Initiative (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527.
REFERENCES
Sims, R., van der Lee, S.J., Naj, A.C., Bellenguez, C., Badarinarayan, N., Jakobsdottir, J., Kunkle, B.W., Boland, A., Raybould, R., Bis, J.C., et al.; ARUK Consortium; GERAD/PERADES, CHARGE, ADGC, EADI (2017). Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384.
Baik, S.H., Kang, S., Lee, W., Choi, H., Chung, S., Kim, J.I., and Mook-Jung, I. (2019). A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 30, this issue, 493–507.
Ulland, T.K., Song, W.M., Huang, S.C., Ulrich, J.D., Sergushichev, A., Beatty, W.L., Loboda, A.A., Zhou, Y., Cairns, N.J., Kambal, A., et al. (2017). TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e13.