Microglia in the pathology of Alzheimer's disease

Research Article
Open access

Microglia in the pathology of Alzheimer's disease

Yufan Wang 1*
  • 1 Beijing Huiwen Middle School    
  • *corresponding author arryfan@sina.com
Published on 20 December 2023 | https://doi.org/10.54254/2753-8818/22/20230968
TNS Vol.22
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-83558-217-6
ISBN (Online): 978-1-83558-218-3

Abstract

As the most common neurodegenerative disease, Alzheimer's disease (AD) is troubling countless middle-aged and elderly people. Countless scientists devote themselves to the study of AD in order to help sufferers live happier life. One of the most striking features of AD is the large number of activated microglia around amyloid plaques. This suggests that microglia play an important role in the pathogenesis of AD. But conflicting views have emerged about the specific role of microglia. Some have found that microglia, boosted by proteins such as TREM2 and APOE, can clear plaques in the brain, preventing AD from occurring. Others, however, have found that complement activation mechanisms cause microglia to excessively clear synapses to exacerbate the pathology of AD. This review introduces two opposite opinions about microglia’s effects in Alzheimer's disease, which is actually about the theory about how TREM2 and microglia mitigate Alzheimer's disease, and why complement and microglia can exacerbate Alzheimer's disease.

Keywords:

microglia, Alzheimer disease, TREM2, complement, dementia

Export citation

References

[1]. Alzheimer A. 1907. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtliche Medizin. 64:146–148.

[2]. H. Kettenmann, U. K. Hanisch, M. Noda and A. Verkhratsky. Physiol Rev 2011 Vol. 91 Issue 2 Pages 464-466

[3]. Nayak D., Roth T.L., and McGavern D.B. 2014. Microglia development and function. Annu. Rev. Immunol. 32:367–402. 10.1146/annurev-immunol-032713-120240

[4]. Colonna M., and Butovsky O. 2017. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 35:441–468. 10.1146/annurev-immunol-051116-052358

[5]. Schafer D.P., Lehrman E.K., Kautzman A.G., Koyama R., Mardinly A.R., Yamasaki R., Ransohoff R.M., Greenberg M.E., Barres B.A., and Stevens B. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 74:691–705. 10.1016/j.neuron.2012.03.026

[6]. Frost J.L., and Schafer D.P.. 2016. Microglia: Architects of the Developing Nervous System. Trends Cell Biol. 26:587–597. 10.1016/j.tcb.2016.02.006

[7]. Baruch K. Deczkowska A.Rosenzweig N.Tsitsou-Kampeli A.Sharif A.M. Matcovitch-Natan O. Kertser A. David E. Amit I. Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 2016; 22: 135-137

[8]. Deardorff W.J. Grossberg G.T. Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics. Expert Rev. Neurother. 2017; 17: 17-32

[9]. Guillot-Sestier M.V. Doty K.R. Gate D. Rodriguez Jr., J. Leung B.P. Rezai-Zadeh K. Town T. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015; 85: 534-548

[10]. Lai A.Y. McLaurin J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 2012; 7: 165-176

[11]. Simard A.R. Soulet D. Gowing G. Julien J.P. Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006; 49: 489-502

[12]. Wang Y. Ulland T.K. Ulrich J.D. Song W. Tzaferis J.A. Hole J.T. Yuan P. Mahan T.E. Shi Y. Gilfillan S. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 2016; 213: 667-675

[13]. Heppner F.L. Ransohoff R.M. Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 2015; 16: 358-372

[14]. Tejera D. Heneka M.T. Microglia in Alzheimer’s disease: the good, the bad and the ugly. Curr. Alzheimer Res. 2016; 13: 370-380

[15]. Wang Y. Cella M. Mallinson K. Ulrich J.D. Young K.L. Robinette M.L. Gilfillan S. Krishnan G.M. Sudhakar S. Zinselmeyer B.H. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 2015; 160: 1061-1071

[16]. Yamasaki R. Lu H. Butovsky O. Ohno N. Rietsch A.M. Cialic R. Wu P.M. Doykan C.E. Lin J. Cotleur A.C. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 2014; 211: 1533-1549

[17]. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiology of Aging. 2000;21(3):383–421.

[18]. Hsieh C.L., Koike M., Spusta S.C., Niemi E.C., Yenari M., Nakamura M.C., and Seaman W.E. 2009. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J. Neurochem. 109:1144–1156. 10.1111/j.1471-4159.2009.06042.x

[19]. Zheng H., Jia L., Liu C.C., Rong Z., Zhong L., Yang L., Chen X.F., Fryer J.D., Wang X., Zhang Y.W., et al. 2017. TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway. J. Neurosci. 37:1772–1784. 10.1523/JNEUROSCI.2459-16.2017

[20]. Takahashi K., Rochford C.D., and Neumann H. 2005. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201:647–657. 10.1084/jem.20041611

[21]. Wang Y., Cella M., Mallinson K., Ulrich J.D., Young K.L., Robinette M.L., Gilfillan S., Krishnan G.M., Sudhakar S., Zinselmeyer B.H., et al. 2015. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 160:1061–1071. 10.1016/j.cell.2015.01.049

[22]. McQuadeA, Kang YJ, Hasselmann J, et al. Gene expression and functional deficitsunderlie TREM2-knockout microglia responses in human models of Alzheimer'sdisease. Nat Commun. 2020;11(1):5370. Published 2020 Oct 23.doi:10.1038/s41467-020-19227-5

[23]. Takahashi K., Rochford C.D., and Neumann H. 2005. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201:647–657. 10.1084/jem.20041611

[24]. N’Diaye E.N., Branda C.S., Branda S.S., Nevarez L., Colonna M., Lowell C., Hamerman J.A., and Seaman W.E. 2009. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J. Cell Biol. 184:215–223. 10.1083/jcb.200808080

[25]. Yeh F.L., Wang Y., Tom I., Gonzalez L.C., and Sheng M. 2016. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 91:328–340. 10.1016/j.neuron.2016.06.015

[26]. Condello C., Yuan P., Schain A., and Grutzendler J. 2015. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6:6176 10.1038/ncomms7176

[27]. Bales K.R., Verina T., Dodel R.C., Du Y., Altstiel L., Bender M., Hyslop P., Johnstone E.M., Little S.P., Cummins D.J., et al. 1997b Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17:263–264. 10.1038/ng1197-263

[28]. Bien-Ly N., Gillespie A.K., Walker D., Yoon S.Y., and Huang Y. 2012. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci. 32:4803–4811. 10.1523/JNEUROSCI.0033-12.2012

[29]. Wang Y., Ulland T.K., Ulrich J.D., Song W., Tzaferis J.A., Hole J.T., Yuan P., Mahan T.E., Shi Y., Gilfillan S., et al. 2016. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213:667–675. 10.1084/jem.20151948

[30]. J Cell Biol. 2018 Feb 5; 217(2): 459–472. doi: 10.1083/jcb.201709069

[31]. Liddelow 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. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 541:481–487. 10.1038/nature21029

[32]. Wu Y., Dissing-Olesen L., MacVicar B.A., and Stevens B. 2015. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol. 36:605–613. 10.1016/j.it.2015.08.008

[33]. Leyns C.E.G., and Holtzman D.M. 2017. Glial contributions to neurodegeneration in tauopathies. Mol. Neurodegener. 12:50 10.1186/s13024-017-0192-x

[34]. Shen Y, Meri S. Yin and Yang: complement activation and regulation in Alzheimer’s disease. Progress in Neurobiology. 2003;70(6):463–472.

[35]. Barnum SR. Complement biosynthesis in the central nervous system. Critical Reviews in Oral Biology and Medicine. 1995;6(2):132–146.

[36]. Nataf S, Stahel PF, Davoust N, Barnum SR. Complement anaphylatoxin receptors on neurons: new tricks for old receptors? Trends in Neurosciences. 1999;22(9):397–402.

[37]. Gasque P, Fontaine M, Morgan BP. Complement expression in human brain: biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. Journal of Immunology. 1995;154(9):4726–4733.

[38]. Morgan BP, Gasque P. Expression of complement in the brain: role in health and disease. Immunology Today. 1996;17(10):461–466.

[39]. Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ. Localization and cell association of C1q in Alzheimer’s disease brain. Experimental Neurology.

[40]. Fonseca M.I., Zhou J., Botto M., and Tenner A.J. 2004. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 24:6457–6465. 10.1523/JNEUROSCI.0901-04.2004

[41]. Hong 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. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 352:712–716.

[42]. Schafer D.P., Lehrman E.K., Kautzman A.G., Koyama R., Mardinly A.R., Yamasaki R., Ransohoff R.M., Greenberg M.E., Barres B.A., and Stevens B. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 74:691–705. 10.1016/j.neuron.2012.03.026


Cite this article

Wang,Y. (2023). Microglia in the pathology of Alzheimer's disease. Theoretical and Natural Science,22,152-156.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

Disclaimer/Publisher's Note

The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of EWA Publishing and/or the editor(s). EWA Publishing and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

About volume

Volume title: Proceedings of the 3rd International Conference on Biological Engineering and Medical Science

ISBN:978-1-83558-217-6(Print) / 978-1-83558-218-3(Online)
Editor:Alan Wang
Conference website: https://www.icbiomed.org/
Conference date: 2 September 2023
Series: Theoretical and Natural Science
Volume number: Vol.22
ISSN:2753-8818(Print) / 2753-8826(Online)

© 2024 by the author(s). Licensee EWA Publishing, Oxford, UK. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Authors who publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See Open access policy for details).

References

[1]. Alzheimer A. 1907. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtliche Medizin. 64:146–148.

[2]. H. Kettenmann, U. K. Hanisch, M. Noda and A. Verkhratsky. Physiol Rev 2011 Vol. 91 Issue 2 Pages 464-466

[3]. Nayak D., Roth T.L., and McGavern D.B. 2014. Microglia development and function. Annu. Rev. Immunol. 32:367–402. 10.1146/annurev-immunol-032713-120240

[4]. Colonna M., and Butovsky O. 2017. Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annu. Rev. Immunol. 35:441–468. 10.1146/annurev-immunol-051116-052358

[5]. Schafer D.P., Lehrman E.K., Kautzman A.G., Koyama R., Mardinly A.R., Yamasaki R., Ransohoff R.M., Greenberg M.E., Barres B.A., and Stevens B. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 74:691–705. 10.1016/j.neuron.2012.03.026

[6]. Frost J.L., and Schafer D.P.. 2016. Microglia: Architects of the Developing Nervous System. Trends Cell Biol. 26:587–597. 10.1016/j.tcb.2016.02.006

[7]. Baruch K. Deczkowska A.Rosenzweig N.Tsitsou-Kampeli A.Sharif A.M. Matcovitch-Natan O. Kertser A. David E. Amit I. Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 2016; 22: 135-137

[8]. Deardorff W.J. Grossberg G.T. Targeting neuroinflammation in Alzheimer’s disease: evidence for NSAIDs and novel therapeutics. Expert Rev. Neurother. 2017; 17: 17-32

[9]. Guillot-Sestier M.V. Doty K.R. Gate D. Rodriguez Jr., J. Leung B.P. Rezai-Zadeh K. Town T. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron. 2015; 85: 534-548

[10]. Lai A.Y. McLaurin J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol. 2012; 7: 165-176

[11]. Simard A.R. Soulet D. Gowing G. Julien J.P. Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006; 49: 489-502

[12]. Wang Y. Ulland T.K. Ulrich J.D. Song W. Tzaferis J.A. Hole J.T. Yuan P. Mahan T.E. Shi Y. Gilfillan S. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 2016; 213: 667-675

[13]. Heppner F.L. Ransohoff R.M. Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 2015; 16: 358-372

[14]. Tejera D. Heneka M.T. Microglia in Alzheimer’s disease: the good, the bad and the ugly. Curr. Alzheimer Res. 2016; 13: 370-380

[15]. Wang Y. Cella M. Mallinson K. Ulrich J.D. Young K.L. Robinette M.L. Gilfillan S. Krishnan G.M. Sudhakar S. Zinselmeyer B.H. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 2015; 160: 1061-1071

[16]. Yamasaki R. Lu H. Butovsky O. Ohno N. Rietsch A.M. Cialic R. Wu P.M. Doykan C.E. Lin J. Cotleur A.C. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 2014; 211: 1533-1549

[17]. Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiology of Aging. 2000;21(3):383–421.

[18]. Hsieh C.L., Koike M., Spusta S.C., Niemi E.C., Yenari M., Nakamura M.C., and Seaman W.E. 2009. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J. Neurochem. 109:1144–1156. 10.1111/j.1471-4159.2009.06042.x

[19]. Zheng H., Jia L., Liu C.C., Rong Z., Zhong L., Yang L., Chen X.F., Fryer J.D., Wang X., Zhang Y.W., et al. 2017. TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway. J. Neurosci. 37:1772–1784. 10.1523/JNEUROSCI.2459-16.2017

[20]. Takahashi K., Rochford C.D., and Neumann H. 2005. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201:647–657. 10.1084/jem.20041611

[21]. Wang Y., Cella M., Mallinson K., Ulrich J.D., Young K.L., Robinette M.L., Gilfillan S., Krishnan G.M., Sudhakar S., Zinselmeyer B.H., et al. 2015. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell. 160:1061–1071. 10.1016/j.cell.2015.01.049

[22]. McQuadeA, Kang YJ, Hasselmann J, et al. Gene expression and functional deficitsunderlie TREM2-knockout microglia responses in human models of Alzheimer'sdisease. Nat Commun. 2020;11(1):5370. Published 2020 Oct 23.doi:10.1038/s41467-020-19227-5

[23]. Takahashi K., Rochford C.D., and Neumann H. 2005. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201:647–657. 10.1084/jem.20041611

[24]. N’Diaye E.N., Branda C.S., Branda S.S., Nevarez L., Colonna M., Lowell C., Hamerman J.A., and Seaman W.E. 2009. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J. Cell Biol. 184:215–223. 10.1083/jcb.200808080

[25]. Yeh F.L., Wang Y., Tom I., Gonzalez L.C., and Sheng M. 2016. TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 91:328–340. 10.1016/j.neuron.2016.06.015

[26]. Condello C., Yuan P., Schain A., and Grutzendler J. 2015. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6:6176 10.1038/ncomms7176

[27]. Bales K.R., Verina T., Dodel R.C., Du Y., Altstiel L., Bender M., Hyslop P., Johnstone E.M., Little S.P., Cummins D.J., et al. 1997b Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat. Genet. 17:263–264. 10.1038/ng1197-263

[28]. Bien-Ly N., Gillespie A.K., Walker D., Yoon S.Y., and Huang Y. 2012. Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. J. Neurosci. 32:4803–4811. 10.1523/JNEUROSCI.0033-12.2012

[29]. Wang Y., Ulland T.K., Ulrich J.D., Song W., Tzaferis J.A., Hole J.T., Yuan P., Mahan T.E., Shi Y., Gilfillan S., et al. 2016. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213:667–675. 10.1084/jem.20151948

[30]. J Cell Biol. 2018 Feb 5; 217(2): 459–472. doi: 10.1083/jcb.201709069

[31]. Liddelow 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. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 541:481–487. 10.1038/nature21029

[32]. Wu Y., Dissing-Olesen L., MacVicar B.A., and Stevens B. 2015. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol. 36:605–613. 10.1016/j.it.2015.08.008

[33]. Leyns C.E.G., and Holtzman D.M. 2017. Glial contributions to neurodegeneration in tauopathies. Mol. Neurodegener. 12:50 10.1186/s13024-017-0192-x

[34]. Shen Y, Meri S. Yin and Yang: complement activation and regulation in Alzheimer’s disease. Progress in Neurobiology. 2003;70(6):463–472.

[35]. Barnum SR. Complement biosynthesis in the central nervous system. Critical Reviews in Oral Biology and Medicine. 1995;6(2):132–146.

[36]. Nataf S, Stahel PF, Davoust N, Barnum SR. Complement anaphylatoxin receptors on neurons: new tricks for old receptors? Trends in Neurosciences. 1999;22(9):397–402.

[37]. Gasque P, Fontaine M, Morgan BP. Complement expression in human brain: biosynthesis of terminal pathway components and regulators in human glial cells and cell lines. Journal of Immunology. 1995;154(9):4726–4733.

[38]. Morgan BP, Gasque P. Expression of complement in the brain: role in health and disease. Immunology Today. 1996;17(10):461–466.

[39]. Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ. Localization and cell association of C1q in Alzheimer’s disease brain. Experimental Neurology.

[40]. Fonseca M.I., Zhou J., Botto M., and Tenner A.J. 2004. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer’s disease. J. Neurosci. 24:6457–6465. 10.1523/JNEUROSCI.0901-04.2004

[41]. Hong 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. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 352:712–716.

[42]. Schafer D.P., Lehrman E.K., Kautzman A.G., Koyama R., Mardinly A.R., Yamasaki R., Ransohoff R.M., Greenberg M.E., Barres B.A., and Stevens B. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 74:691–705. 10.1016/j.neuron.2012.03.026