Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
Abstract
:1. Introduction
Innate Immune Signaling Pathways in the Central Nervous System
2. Neuroinflammation, Innate Immunity, and AD: A Complex Relationship
2.1. Microglia
2.2. Astrocytes
2.3. Endothelial Cells
3. Cell Death and AD
3.1. Pyroptosis in AD
3.2. Apoptosis in AD
3.3. Necroptosis in AD
3.4. PANoptosis in AD
4. Cytokines and Chemokines as Modulators of Neuroinflammation
5. Therapeutic Implications of Innate Immune Involvement for AD Management
6. Discussion and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
- Collaborators, G.B.D.D. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019, 18, 88–106. [Google Scholar] [CrossRef] [Green Version]
- Maccioni, R.B.; Rojo, L.E.; Fernández, J.A.; Kuljis, R.O. The role of neuroimmunomodulation in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 2009, 1153, 240–246. [Google Scholar] [CrossRef] [PubMed]
- Jiang, C.; Zou, X.; Zhu, R.; Shi, Y.; Wu, Z.; Zhao, F.; Chen, L. The correlation between accumulation of amyloid beta with enhanced neuroinflammation and cognitive impairment after intraventricular hemorrhage. J. Neurosurg. 2018, 131, 54–63. [Google Scholar] [CrossRef] [PubMed]
- Moujalled, D.; Strasser, A.; Liddell, J.R. Molecular mechanisms of cell death in neurological diseases. Cell Death Differ. 2021, 28, 2029–2044. [Google Scholar] [CrossRef] [PubMed]
- Jack, C.R., Jr.; Knopman, D.S.; Jagust, W.J.; Shaw, L.M.; Aisen, P.S.; Weiner, M.W.; Petersen, R.C.; Trojanowski, J.Q. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010, 9, 119–128. [Google Scholar] [CrossRef] [Green Version]
- Chen, G.F.; Xu, T.H.; Yan, Y.; Zhou, Y.R.; Jiang, Y.; Melcher, K.; Xu, H.E. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta. Pharm. Sin. 2017, 38, 1205–1235. [Google Scholar] [CrossRef]
- Chasseigneaux, S.; Allinquant, B. Functions of Abeta, sAPPalpha and sAPPbeta: Similarities and differences. J. Neurochem. 2012, 120 (Suppl. S1), 99–108. [Google Scholar] [CrossRef]
- Katzmarski, N.; Ziegler-Waldkirch, S.; Scheffler, N.; Witt, C.; Abou-Ajram, C.; Nuscher, B.; Prinz, M.; Haass, C.; Meyer-Luehmann, M. Abeta oligomers trigger and accelerate Abeta seeding. Brain Pathol. 2020, 30, 36–45. [Google Scholar] [CrossRef] [Green Version]
- Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015, 14, 388–405. [Google Scholar] [CrossRef] [Green Version]
- Wesseling, H.; Mair, W.; Kumar, M.; Schlaffner, C.N.; Tang, S.; Beerepoot, P.; Fatou, B.; Guise, A.J.; Cheng, L.; Takeda, S.; et al. Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease. Cell 2020, 183, 1699–1713.e13. [Google Scholar] [CrossRef]
- Alonso, A.D.; Cohen, L.S.; Corbo, C.; Morozova, V.; ElIdrissi, A.; Phillips, G.; Kleiman, F.E. Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability. Front. Cell Neurosci. 2018, 12, 338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fiandaca, M.S.; Kapogiannis, D.; Mapstone, M.; Boxer, A.; Eitan, E.; Schwartz, J.B.; Abner, E.L.; Petersen, R.C.; Federoff, H.J.; Miller, B.L.; et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 2015, 11, 600–607.e1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jia, L.; Qiu, Q.; Zhang, H.; Chu, L.; Du, Y.; Zhang, J.; Zhou, C.; Liang, F.; Shi, S.; Wang, S.; et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid. Alzheimers Dement. 2019, 15, 1071–1080. [Google Scholar] [CrossRef] [PubMed]
- Cortes, N.; Andrade, V.; Guzman-Martinez, L.; Estrella, M.; Maccioni, R.B. Neuroimmune Tau Mechanisms: Their Role in the Progression of Neuronal Degeneration. Int. J. Mol. Sci. 2018, 19, 956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weingarten, M.D.; Lockwood, A.H.; Hwo, S.Y.; Kirschner, M.W. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 1975, 72, 1858–1862. [Google Scholar] [CrossRef] [Green Version]
- Drechsel, D.N.; Hyman, A.A.; Cobb, M.H.; Kirschner, M.W. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol. Biol. Cell 1992, 3, 1141–1154. [Google Scholar] [CrossRef] [Green Version]
- Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018, 25, 486–541. [Google Scholar] [CrossRef]
- Kuriakose, T.; Man, S.M.; Malireddi, R.K.; Karki, R.; Kesavardhana, S.; Place, D.E.; Neale, G.; Vogel, P.; Kanneganti, T.D. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 2016, 1, aag2045. [Google Scholar] [CrossRef] [Green Version]
- Malireddi, R.K.S.; Karki, R.; Sundaram, B.; Kancharana, B.; Lee, S.; Samir, P.; Kanneganti, T.D. Inflammatory Cell Death, PANoptosis, Mediated by Cytokines in Diverse Cancer Lineages Inhibits Tumor Growth. Immunohorizons 2021, 5, 568–580. [Google Scholar] [CrossRef]
- Kesavardhana, S.; Malireddi, R.K.S.; Burton, A.R.; Porter, S.N.; Vogel, P.; Pruett-Miller, S.M.; Kanneganti, T.-D. The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development. J. Biol. Chem. 2020, 295, 8325–8330. [Google Scholar] [CrossRef]
- Banoth, B.; Tuladhar, S.; Karki, R.; Sharma, B.R.; Briard, B.; Kesavardhana, S.; Burton, A.; Kanneganti, T.-D. ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis). J. Biol. Chem. 2020, 295, 18276–18283. [Google Scholar] [CrossRef] [PubMed]
- Christgen, S.; Zheng, M.; Kesavardhana, S.; Karki, R.; Malireddi, R.K.S.; Banoth, B.; Place, D.E.; Briard, B.; Sharma, B.R.; Tuladhar, S.; et al. Identification of the PANoptosome: A molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis). Front. Cell. Infect. Microbiol. 2020, 10, 237. [Google Scholar] [CrossRef] [PubMed]
- Karki, R.; Sharma, B.R.; Lee, E.; Banoth, B.; Malireddi, R.K.S.; Samir, P.; Tuladhar, S.; Mummareddy, H.; Burton, A.R.; Vogel, P.; et al. Interferon regulatory factor 1 regulates PANoptosis to prevent colorectal cancer. JCI Insight 2020, 5. [Google Scholar] [CrossRef] [PubMed]
- Zheng, M.; Williams, E.P.; Malireddi, R.K.S.; Karki, R.; Banoth, B.; Burton, A.; Webby, R.; Channappanavar, R.; Jonsson, C.B.; Kanneganti, T.-D. Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection. J. Biol. Chem. 2020, 295, 14040–14052. [Google Scholar] [CrossRef]
- Gurung, P.; Burton, A.; Kanneganti, T.D. NLRP3 inflammasome plays a redundant role with caspase 8 to promote IL-1beta-mediated osteomyelitis. Proc. Natl. Acad. Sci. USA 2016, 113, 4452–4457. [Google Scholar] [CrossRef] [Green Version]
- Lukens, J.R.; Gurung, P.; Vogel, P.; Johnson, G.R.; Carter, R.A.; McGoldrick, D.J.; Bandi, S.R.; Calabrese, C.R.; Vande Walle, L.; Lamkanfi, M.; et al. Dietary modulation of the microbiome affects autoinflammatory disease. Nature 2014, 516, 246–249. [Google Scholar] [CrossRef] [Green Version]
- Malireddi, R.K.; Ippagunta, S.; Lamkanfi, M.; Kanneganti, T.D. Cutting edge: Proteolytic inactivation of poly(ADP-ribose) polymerase 1 by the Nlrp3 and Nlrc4 inflammasomes. J. Immunol. 2010, 185, 3127–3130. [Google Scholar] [CrossRef] [Green Version]
- Malireddi, R.K.S.; Gurung, P.; Kesavardhana, S.; Samir, P.; Burton, A.; Mummareddy, H.; Vogel, P.; Pelletier, S.; Burgula, S.; Kanneganti, T.D. Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity-independent pyroptosis, apoptosis, necroptosis, and inflammatory disease. J. Exp. Med. 2020, 217. [Google Scholar] [CrossRef]
- Malireddi, R.K.S.; Kesavardhana, S.; Karki, R.; Kancharana, B.; Burton, A.R.; Kanneganti, T.D. RIPK1 Distinctly Regulates Yersinia-Induced Inflammatory Cell Death, PANoptosis. Immunohorizons 2020, 4, 789–796. [Google Scholar] [CrossRef]
- Zheng, M.; Karki, R.; Vogel, P.; Kanneganti, T.D. Caspase-6 is a key regulator of innate immunity, inflammasome activation and host defense. Cell 2020, 181, 674–687.e13. [Google Scholar] [CrossRef]
- Karki, R.; Sharma, B.R.; Tuladhar, S.; Williams, E.P.; Zalduondo, L.; Samir, P.; Zheng, M.; Sundaram, B.; Banoth, B.; Malireddi, R.K.S.; et al. Synergism of TNF-alpha and IFN-gamma Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes. Cell 2021, 184, 149–168.e17. [Google Scholar] [CrossRef] [PubMed]
- Malireddi, R.K.S.; Gurung, P.; Mavuluri, J.; Dasari, T.K.; Klco, J.M.; Chi, H.; Kanneganti, T.D. TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J. Exp. Med. 2018, 215, 1023–1034. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lamkanfi, M.; Kanneganti, T.D.; Van Damme, P.; Vanden Berghe, T.; Vanoverberghe, I.; Vandekerckhove, J.; Vandenabeele, P.; Gevaert, K.; Nunez, G. Targeted peptidecentric proteomics reveals caspase-7 as a substrate of the caspase-1 inflammasomes. Mol. Cell Proteom. 2008, 7, 2350–2363. [Google Scholar] [CrossRef] [Green Version]
- Gurung, P.; Anand, P.K.; Malireddi, R.K.; Vande Walle, L.; Van Opdenbosch, N.; Dillon, C.P.; Weinlich, R.; Green, D.R.; Lamkanfi, M.; Kanneganti, T.D. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J. Immunol. 2014, 192, 1835–1846. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.; Karki, R.; Wang, Y.; Nguyen, L.N.; Kalathur, R.C.; Kanneganti, T.D. AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence. Nature 2021, 597, 415–419. [Google Scholar] [CrossRef] [PubMed]
- Karki, R.; Sundaram, B.; Sharma, B.R.; Lee, S.; Malireddi, R.K.S.; Nguyen, L.N.; Christgen, S.; Zheng, M.; Wang, Y.; Samir, P.; et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. Cell Rep. 2021, 37, 109858. [Google Scholar] [CrossRef]
- Mattson, M.P. Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell Biol. 2000, 1, 120–129. [Google Scholar] [CrossRef]
- McKenzie, B.A.; Dixit, V.M.; Power, C. Fiery Cell Death: Pyroptosis in the Central Nervous System. Trends Neurosci. 2020, 43, 55–73. [Google Scholar] [CrossRef]
- Cookson, B.T.; Brennan, M.A. Pro-inflammatory programmed cell death. Trends Microbiol. 2001, 9, 113–114. [Google Scholar] [CrossRef]
- Martinon, F.; Burns, K.; Tschopp, J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 2002, 10, 417–426. [Google Scholar] [CrossRef]
- Gong, Y.; Fan, Z.; Luo, G.; Yang, C.; Huang, Q.; Fan, K.; Cheng, H.; Jin, K.; Ni, Q.; Yu, X.; et al. The role of necroptosis in cancer biology and therapy. Mol. Cancer 2019, 18, 100. [Google Scholar] [CrossRef] [Green Version]
- Nailwal, H.; Chan, F.K. Necroptosis in anti-viral inflammation. Cell Death Differ. 2019, 26, 4–13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kang, T.B.; Ben-Moshe, T.; Varfolomeev, E.E.; Pewzner-Jung, Y.; Yogev, N.; Jurewicz, A.; Waisman, A.; Brenner, O.; Haffner, R.; Gustafsson, E.; et al. Caspase-8 serves both apoptotic and nonapoptotic roles. J. Immunol. 2004, 173, 2976–2984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shan, B.; Pan, H.; Najafov, A.; Yuan, J. Necroptosis in development and diseases. Genes Dev. 2018, 32, 327–340. [Google Scholar] [CrossRef] [PubMed]
- Ofengeim, D.; Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 2013, 14, 727–736. [Google Scholar] [CrossRef] [PubMed]
- Weinlich, R.; Oberst, A.; Beere, H.M.; Green, D.R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 2017, 18, 127–136. [Google Scholar] [CrossRef]
- Kanneganti, T.D. Intracellular innate immune receptors: Life inside the cell. Immunol Rev. 2020, 297, 5–12. [Google Scholar] [CrossRef]
- Norris, G.T.; Kipnis, J. Immune cells and CNS physiology: Microglia and beyond. J. Exp. Med. 2019, 216, 60–70. [Google Scholar] [CrossRef]
- Ajami, B.; Bennett, J.L.; Krieger, C.; Tetzlaff, W.; Rossi, F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 2007, 10, 1538–1543. [Google Scholar] [CrossRef]
- Tay, T.L.; Hagemeyer, N.; Prinz, M. The force awakens: Insights into the origin and formation of microglia. Curr. Opin. Neurobiol. 2016, 39, 30–37. [Google Scholar] [CrossRef]
- Elmore, M.R.; Najafi, A.R.; Koike, M.A.; Dagher, N.N.; Spangenberg, E.E.; Rice, R.A.; Kitazawa, M.; Matusow, B.; Nguyen, H.; West, B.L.; et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 2014, 82, 380–397. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Clayton, K.A.; Van Enoo, A.A.; Ikezu, T. Alzheimer’s Disease: The Role of Microglia in Brain Homeostasis and Proteopathy. Front. Neurosci. 2017, 11, 680. [Google Scholar] [CrossRef] [PubMed]
- Hanisch, U.K.; Kettenmann, H. Microglia: Active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 2007, 10, 1387–1394. [Google Scholar] [CrossRef]
- Lenz, K.M.; Nelson, L.H. Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. Front. Immunol. 2018, 9, 698. [Google Scholar] [CrossRef] [Green Version]
- Sochocka, M.; Diniz, B.S.; Leszek, J. Inflammatory Response in the CNS: Friend or Foe? Mol. Neurobiol. 2017, 54, 8071–8089. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rea, I.M.; Gibson, D.S.; McGilligan, V.; McNerlan, S.E.; Alexander, H.D.; Ross, O.A. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front. Immunol. 2018, 9, 586. [Google Scholar] [CrossRef]
- Hodges, A.K.; Piers, T.M.; Collier, D.; Cousins, O.; Pocock, J.M. Pathways linking Alzheimer’s disease risk genes expressed highly in microglia. Neuroimmunol. Neuroinflammation 2021, 8, 245–268. [Google Scholar] [CrossRef]
- Baroja-Mazo, A.; Martin-Sanchez, F.; Gomez, A.I.; Martinez, C.M.; Amores-Iniesta, J.; Compan, V.; Barbera-Cremades, M.; Yague, J.; Ruiz-Ortiz, E.; Anton, J.; et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 2014, 15, 738–748. [Google Scholar] [CrossRef]
- Koenigsknecht-Talboo, J.; Landreth, G.E. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J. Neurosci. 2005, 25, 8240–8249. [Google Scholar] [CrossRef] [PubMed]
- Sondag, C.M.; Dhawan, G.; Combs, C.K. Beta amyloid oligomers and fibrils stimulate differential activation of primary microglia. J. Neuroinflammation 2009, 6, 1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kigerl, K.A.; de Rivero Vaccari, J.P.; Dietrich, W.D.; Popovich, P.G.; Keane, R.W. Pattern recognition receptors and central nervous system repair. Exp. Neurol. 2014, 258, 5–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Heneka, M.T.; Kummer, M.P.; Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 2014, 14, 463–477. [Google Scholar] [CrossRef] [PubMed]
- McDonough, A.; Lee, R.V.; Weinstein, J.R. Microglial Interferon Signaling and White Matter. Neurochem. Res. 2017, 42, 2625–2638. [Google Scholar] [CrossRef] [PubMed]
- Nagele, R.G.; Wegiel, J.; Venkataraman, V.; Imaki, H.; Wang, K.C.; Wegiel, J. Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol. Aging 2004, 25, 663–674. [Google Scholar] [CrossRef] [PubMed]
- Serrano-Pozo, A.; Mielke, M.L.; Gomez-Isla, T.; Betensky, R.A.; Growdon, J.H.; Frosch, M.P.; Hyman, B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am. J. Pathol. 2011, 179, 1373–1384. [Google Scholar] [CrossRef]
- Bamberger, M.E.; Harris, M.E.; McDonald, D.R.; Husemann, J.; Landreth, G.E. A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J. Neurosci. 2003, 23, 2665–2674. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ries, M.; Sastre, M. Mechanisms of Abeta Clearance and Degradation by Glial Cells. Front. Aging Neurosci. 2016, 8, 160. [Google Scholar] [CrossRef] [Green Version]
- Tahara, K.; Kim, H.D.; Jin, J.J.; Maxwell, J.A.; Li, L.; Fukuchi, K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 2006, 129, 3006–3019. [Google Scholar] [CrossRef] [Green Version]
- Wilkinson, K.; El Khoury, J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer’s disease. Int. J. Alzheimers Dis. 2012, 2012, 489456. [Google Scholar] [CrossRef] [Green Version]
- Reed-Geaghan, E.G.; Savage, J.C.; Hise, A.G.; Landreth, G.E. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J. Neurosci. 2009, 29, 11982–11992. [Google Scholar] [CrossRef]
- Chen, K.; Iribarren, P.; Hu, J.; Chen, J.; Gong, W.; Cho, E.H.; Lockett, S.; Dunlop, N.M.; Wang, J.M. Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J. Biol. Chem. 2006, 281, 3651–3659. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hickman, S.E.; Allison, E.K.; El Khoury, J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J. Neurosci. 2008, 28, 8354–8360. [Google Scholar] [CrossRef] [PubMed]
- Theriault, P.; ElAli, A.; Rivest, S. The dynamics of monocytes and microglia in Alzheimer’s disease. Alzheimers Res. 2015, 7, 41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Frackowiak, J.; Wisniewski, H.M.; Wegiel, J.; Merz, G.S.; Iqbal, K.; Wang, K.C. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol. 1992, 84, 225–233. [Google Scholar] [CrossRef] [PubMed]
- Krabbe, G.; Halle, A.; Matyash, V.; Rinnenthal, J.L.; Eom, G.D.; Bernhardt, U.; Miller, K.R.; Prokop, S.; Kettenmann, H.; Heppner, F.L. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS ONE 2013, 8, e60921. [Google Scholar] [CrossRef] [PubMed]
- Lok, K.; Zhao, H.; Shen, H.; Wang, Z.; Gao, X.; Zhao, W.; Yin, M. Characterization of the APP/PS1 mouse model of Alzheimer’s disease in senescence accelerated background. Neurosci. Lett. 2013, 557, 84–89. [Google Scholar] [CrossRef] [PubMed]
- McDonald, C.L.; Hennessy, E.; Rubio-Araiz, A.; Keogh, B.; McCormack, W.; McGuirk, P.; Reilly, M.; Lynch, M.A. Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer’s disease. Brain Behav. Immun. 2016, 58, 191–200. [Google Scholar] [CrossRef]
- Vollmar, P.; Kullmann, J.S.; Thilo, B.; Claussen, M.C.; Rothhammer, V.; Jacobi, H.; Sellner, J.; Nessler, S.; Korn, T.; Hemmer, B. Active immunization with amyloid-beta 1-42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. J. Immunol. 2010, 185, 6338–6347. [Google Scholar] [CrossRef] [Green Version]
- Jana, M.; Palencia, C.A.; Pahan, K. Fibrillar amyloid-beta peptides activate microglia via TLR2: Implications for Alzheimer’s disease. J. Immunol. 2008, 181, 7254–7262. [Google Scholar] [CrossRef]
- Liu, S.; Liu, Y.; Hao, W.; Wolf, L.; Kiliaan, A.J.; Penke, B.; Rube, C.E.; Walter, J.; Heneka, M.T.; Hartmann, T.; et al. TLR2 is a primary receptor for Alzheimer’s amyloid beta peptide to trigger neuroinflammatory activation. J. Immunol. 2012, 188, 1098–1107. [Google Scholar] [CrossRef] [Green Version]
- Griciuc, A.; Tanzi, R.E. The role of innate immune genes in Alzheimer’s disease. Curr. Opin. Neurol. 2021, 34, 228–236. [Google Scholar] [CrossRef] [PubMed]
- Wightman, D.P.; Jansen, I.E.; Savage, J.E.; Shadrin, A.A.; Bahrami, S.; Holland, D.; Rongve, A.; Borte, S.; Winsvold, B.S.; Drange, O.K.; et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat. Genet. 2021, 53, 1276–1282. [Google Scholar] [CrossRef] [PubMed]
- Chatila, Z.K.; Bradshaw, E.M. Alzheimer’s Disease Genetics: A Dampened Microglial Response? Neuroscientist 2021, 10738584211024531. [Google Scholar] [CrossRef]
- Boutajangout, A.; Wisniewski, T. The innate immune system in Alzheimer’s disease. Int. J. Cell Biol. 2013, 2013, 576383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Takatori, S.; Wang, W.; Iguchi, A.; Tomita, T. Genetic Risk Factors for Alzheimer Disease: Emerging Roles of Microglia in Disease Pathomechanisms. In Advances in Experimental Medicine and Biology; Springer: Cham, Switzerland, 2019; Volume 1118. [Google Scholar]
- Song, M.; Jin, J.; Lim, J.E.; Kou, J.; Pattanayak, A.; Rehman, J.A.; Kim, H.D.; Tahara, K.; Lalonde, R.; Fukuchi, K. TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J. Neuroinflammation 2011, 8, 92. [Google Scholar] [CrossRef] [Green Version]
- Kaushal, V.; Dye, R.; Pakavathkumar, P.; Foveau, B.; Flores, J.; Hyman, B.; Ghetti, B.; Koller, B.H.; LeBlanc, A.C. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ. 2015, 22, 1676–1686. [Google Scholar] [CrossRef] [Green Version]
- Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.C.; et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2013, 493, 674–678. [Google Scholar] [CrossRef]
- Freeman, L.; Guo, H.; David, C.N.; Brickey, W.J.; Jha, S.; Ting, J.P. NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. J. Exp. Med. 2017, 214, 1351–1370. [Google Scholar] [CrossRef] [Green Version]
- Wu, P.J.; Hung, Y.F.; Liu, H.Y.; Hsueh, Y.P. Deletion of the Inflammasome Sensor Aim2 Mitigates Abeta Deposition and Microglial Activation but Increases Inflammatory Cytokine Expression in an Alzheimer Disease Mouse Model. Neuroimmunomodulation 2017, 24, 29–39. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Cheng, J.; Liao, Y.; Xiao, L.; Wu, R.; Zhao, S.; Chen, H.; Hou, B.; Zhang, X.; Liang, C.; Xu, Y.; et al. Autophagy regulates MAVS signaling activation in a phosphorylation-dependent manner in microglia. Cell Death Differ. 2017, 24, 276–287. [Google Scholar] [CrossRef] [PubMed]
- Paula Martorell, V.B.; Schwarz, S.; Heneka, M. cGAS-STING activation in Alzheimer’s disease. Available online: https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwjLvqyar-n3AhWRMM0KHTQCC6gQFnoECAoQAQ&url=https%3A%2F%2Fbonnbrain.de%2Fabstracts%2Fcgas-sting-activation-in-alzheimers-disease%2F&usg=AOvVaw0TTor6dH1LdB53mOX1R5xu (accessed on 24 March 2022).
- De Rivero Vaccari, J.P.; Brand, F.J., 3rd; Sedaghat, C.; Mash, D.C.; Dietrich, W.D.; Keane, R.W. RIG-1 receptor expression in the pathology of Alzheimer’s disease. J. Neuroinflammation 2014, 11, 67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kanneganti, T.D.; Ozoren, N.; Body-Malapel, M.; Amer, A.; Park, J.H.; Franchi, L.; Whitfield, J.; Barchet, W.; Colonna, M.; Vandenabeele, P.; et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 2006, 440, 233–236. [Google Scholar] [CrossRef] [Green Version]
- Mariathasan, S.; Weiss, D.S.; Newton, K.; McBride, J.; O’Rourke, K.; Roose-Girma, M.; Lee, W.P.; Weinrauch, Y.; Monack, D.M.; Dixit, V.M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006, 440, 228–232. [Google Scholar] [CrossRef] [PubMed]
- Martinon, F.; Petrilli, V.; Mayor, A.; Tardivel, A.; Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 2006, 440, 237–241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Franchi, L.; Amer, A.; Body-Malapel, M.; Kanneganti, T.D.; Ozoren, N.; Jagirdar, R.; Inohara, N.; Vandenabeele, P.; Bertin, J.; Coyle, A.; et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat. Immunol. 2006, 7, 576–582. [Google Scholar] [CrossRef]
- Miao, E.A.; Alpuche-Aranda, C.M.; Dors, M.; Clark, A.E.; Bader, M.W.; Miller, S.I.; Aderem, A. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat. Immunol. 2006, 7, 569–575. [Google Scholar] [CrossRef]
- Mariathasan, S.; Newton, K.; Monack, D.M.; Vucic, D.; French, D.M.; Lee, W.P.; Roose-Girma, M.; Erickson, S.; Dixit, V.M. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 2004, 430, 213–218. [Google Scholar] [CrossRef]
- Xu, H.; Yang, J.; Gao, W.; Li, L.; Li, P.; Zhang, L.; Gong, Y.N.; Peng, X.; Xi, J.J.; Chen, S.; et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 2014, 513, 237–241. [Google Scholar] [CrossRef]
- Fernandes-Alnemri, T.; Yu, J.W.; Datta, P.; Wu, J.; Alnemri, E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009, 458, 509–513. [Google Scholar] [CrossRef] [Green Version]
- Hornung, V.; Ablasser, A.; Charrel-Dennis, M.; Bauernfeind, F.; Horvath, G.; Caffrey, D.R.; Latz, E.; Fitzgerald, K.A. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009, 458, 514–518. [Google Scholar] [CrossRef] [Green Version]
- Sharma, B.R.; Kanneganti, T.D. NLRP3 inflammasome in cancer and metabolic diseases. Nat. Immunol. 2021, 22, 550–559. [Google Scholar] [CrossRef] [PubMed]
- Stancu, I.C.; Cremers, N.; Vanrusselt, H.; Couturier, J.; Vanoosthuyse, A.; Kessels, S.; Lodder, C.; Brône, B.; Huaux, F.; Octave, J.N.; et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019, 137, 599–617. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roy, E.R.; Wang, B.; Wan, Y.W.; Chiu, G.; Cole, A.; Yin, Z.; Propson, N.E.; Xu, Y.; Jankowsky, J.L.; Liu, Z.; et al. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J. Clin. Investig. 2020, 130, 1912–1930. [Google Scholar] [CrossRef]
- Forlenza, O.V.; Diniz, B.S.; Talib, L.L.; Mendonca, V.A.; Ojopi, E.B.; Gattaz, W.F.; Teixeira, A.L. Increased serum IL-1beta level in Alzheimer’s disease and mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 2009, 28, 507–512. [Google Scholar] [CrossRef] [PubMed]
- King, E.; O’Brien, J.T.; Donaghy, P.; Morris, C.; Barnett, N.; Olsen, K.; Martin-Ruiz, C.; Taylor, J.P.; Thomas, A.J. Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J. Neurol. Neurosurg. Psychiatry 2018, 89, 339–345. [Google Scholar] [CrossRef] [PubMed]
- Ojala, J.; Alafuzoff, I.; Herukka, S.K.; van Groen, T.; Tanila, H.; Pirttila, T. Expression of interleukin-18 is increased in the brains of Alzheimer’s disease patients. Neurobiol. Aging 2009, 30, 198–209. [Google Scholar] [CrossRef]
- Ng, A.; Tam, W.W.; Zhang, M.W.; Ho, C.S.; Husain, S.F.; McIntyre, R.S.; Ho, R.C. IL-1beta, IL-6, TNF- alpha and CRP in Elderly Patients with Depression or Alzheimer’s disease: Systematic Review and Meta-Analysis. Sci. Rep. 2018, 8, 12050. [Google Scholar] [CrossRef]
- Hansen, D.V.; Hanson, J.E.; Sheng, M. Microglia in Alzheimer’s disease. J. Cell Biol 2018, 217, 459–472. [Google Scholar] [CrossRef] [PubMed]
- Hemonnot, A.L.; Hua, J.; Ulmann, L.; Hirbec, H. Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities. Front. Aging Neurosci. 2019, 11, 233. [Google Scholar] [CrossRef] [Green Version]
- Sarlus, H.; Heneka, M.T. Microglia in Alzheimer’s disease. J. Clin. Investig. 2017, 127, 3240–3249. [Google Scholar] [CrossRef] [PubMed]
- Tejera, D.; Heneka, M.T. Microglia in Alzheimer’s disease: The good, the bad and the ugly. Curr. Alzheimer Res. 2016, 13, 370–380. [Google Scholar] [CrossRef] [PubMed]
- Wyss-Coray, T.; Rogers, J. Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med. 2012, 2, a006346. [Google Scholar] [CrossRef]
- Biber, K.; Neumann, H.; Inoue, K.; Boddeke, H.W. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci. 2007, 30, 596–602. [Google Scholar] [CrossRef] [PubMed]
- Verkhratsky, A.; Nedergaard, M. Physiology of Astroglia. Physiol. Rev. 2018, 98, 239–389. [Google Scholar] [CrossRef] [PubMed]
- Preman, P.; Alfonso-Triguero, M.; Alberdi, E.; Verkhratsky, A.; Arranz, A.M. Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways. Cells 2021, 10, 540. [Google Scholar] [CrossRef] [PubMed]
- Chung, W.S.; Allen, N.J.; Eroglu, C. Astrocytes Control Synapse Formation, Function, and Elimination. Cold Spring Harb. Perspect. Biol. 2015, 7, a020370. [Google Scholar] [CrossRef] [Green Version]
- Sheeler, C.; Rosa, J.G.; Ferro, A.; McAdams, B.; Borgenheimer, E.; Cvetanovic, M. Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator. Int. J. Mol. Sci. 2020, 21, 9188. [Google Scholar] [CrossRef] [PubMed]
- Gamage, R.; Wagnon, I.; Rossetti, I.; Childs, R.; Niedermayer, G.; Chesworth, R.; Gyengesi, E. Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation. Front. Cell Neurosci 2020, 14, 577912. [Google Scholar] [CrossRef]
- Linnerbauer, M.; Wheeler, M.A.; Quintana, F.J. Astrocyte Crosstalk in CNS Inflammation. Neuron 2020, 108, 608–622. [Google Scholar] [CrossRef] [PubMed]
- Giovannoni, F.; Quintana, F.J. The Role of Astrocytes in CNS Inflammation. Trends Immunol. 2020, 41, 805–819. [Google Scholar] [CrossRef]
- Hol, E.M.; Pekny, M. Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr. Opin. Cell Biol. 2015, 32, 121–130. [Google Scholar] [CrossRef] [PubMed]
- Onyango, I.G.; Jauregui, G.V.; Carna, M.; Bennett, J.P., Jr.; Stokin, G.B. Neuroinflammation in Alzheimer’s Disease. Biomedicines 2021, 9, 524. [Google Scholar] [CrossRef] [PubMed]
- Barclay, W.E.; Aggarwal, N.; Deerhake, M.E.; Inoue, M.; Nonaka, T.; Nozaki, K.; Luzum, N.A.; Miao, E.A.; Shinohara, M.L. The AIM2 inflammasome is activated in astrocytes during the late phase of EAE. JCI Insight 2022, 7. [Google Scholar] [CrossRef] [PubMed]
- Johann, S.; Heitzer, M.; Kanagaratnam, M.; Goswami, A.; Rizo, T.; Weis, J.; Troost, D.; Beyer, C. NLRP3 inflammasome is expressed by astrocytes in the SOD1 mouse model of ALS and in human sporadic ALS patients. Glia 2015, 63, 2260–2273. [Google Scholar] [CrossRef] [PubMed]
- Lau, S.F.; Cao, H.; Fu, A.K.Y.; Ip, N.Y. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2020, 117, 25800–25809. [Google Scholar] [CrossRef] [PubMed]
- Nelson, P.T.; Alafuzoff, I.; Bigio, E.H.; Bouras, C.; Braak, H.; Cairns, N.J.; Castellani, R.J.; Crain, B.J.; Davies, P.; Del Tredici, K.; et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J. Neuropathol. Exp. Neurol. 2012, 71, 362–381. [Google Scholar] [CrossRef]
- Ising, C.; Venegas, C.; Zhang, S.; Scheiblich, H.; Schmidt, S.V.; Vieira-Saecker, A.; Schwartz, S.; Albasset, S.; McManus, R.M.; Tejera, D.; et al. NLRP3 inflammasome activation drives tau pathology. Nature 2019, 575, 669–673. [Google Scholar] [CrossRef]
- Venegas, C.; Kumar, S.; Franklin, B.S.; Dierkes, T.; Brinkschulte, R.; Tejera, D.; Vieira-Saecker, A.; Schwartz, S.; Santarelli, F.; Kummer, M.P.; et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 2017, 552, 355–361. [Google Scholar] [CrossRef]
- Bergsbaken, T.; Fink, S.L.; Cookson, B.T. Pyroptosis: Host cell death and inflammation. Nat. Rev. Microbiol. 2009, 7, 99–109. [Google Scholar] [CrossRef] [Green Version]
- Pasparakis, M.; Vandenabeele, P. Necroptosis and its role in inflammation. Nature 2015, 517, 311–320. [Google Scholar] [CrossRef] [PubMed]
- Ding, J.; Wang, K.; Liu, W.; She, Y.; Sun, Q.; Shi, J.; Sun, H.; Wang, D.C.; Shao, F. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 2016, 535, 111–116. [Google Scholar] [CrossRef] [PubMed]
- Liu, X.; Zhang, Z.; Ruan, J.; Pan, Y.; Magupalli, V.G.; Wu, H.; Lieberman, J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 2016, 535, 153–158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sborgi, L.; Ruhl, S.; Mulvihill, E.; Pipercevic, J.; Heilig, R.; Stahlberg, H.; Farady, C.J.; Muller, D.J.; Broz, P.; Hiller, S. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 2016, 35, 1766–1778. [Google Scholar] [CrossRef]
- He, W.T.; Wan, H.; Hu, L.; Chen, P.; Wang, X.; Huang, Z.; Yang, Z.H.; Zhong, C.Q.; Han, J. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res. 2015, 25, 1285–1298. [Google Scholar] [CrossRef]
- Shi, J.; Zhao, Y.; Wang, K.; Shi, X.; Wang, Y.; Huang, H.; Zhuang, Y.; Cai, T.; Wang, F.; Shao, F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 2015, 526, 660–665. [Google Scholar] [CrossRef]
- Schroder, K.; Tschopp, J. The inflammasomes. Cell 2010, 140, 821–832. [Google Scholar] [CrossRef] [Green Version]
- Van de Veerdonk, F.L.; Netea, M.G.; Dinarello, C.A.; Joosten, L.A. Inflammasome activation and IL-1beta and IL-18 processing during infection. Trends Immunol. 2011, 32, 110–116. [Google Scholar] [CrossRef]
- Man, S.M.; Karki, R.; Kanneganti, T.D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol. Rev. 2017, 277, 61–75. [Google Scholar] [CrossRef] [Green Version]
- Han, C.; Yang, Y.; Guan, Q.; Zhang, X.; Shen, H.; Sheng, Y.; Wang, J.; Zhou, X.; Li, W.; Guo, L.; et al. New mechanism of nerve injury in Alzheimer’s disease: β-amyloid-induced neuronal pyroptosis. J. Cell Mol. Med. 2020, 24, 8078–8090. [Google Scholar] [CrossRef]
- Tan, M.S.; Yu, J.T.; Jiang, T.; Zhu, X.C.; Guan, H.S.; Tan, L. IL12/23 p40 inhibition ameliorates Alzheimer’s disease-associated neuropathology and spatial memory in SAMP8 mice. J. Alzheimers Dis. 2014, 38, 633–646. [Google Scholar] [CrossRef] [PubMed]
- Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol. 2008, 9, 857–865. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maccioni, R.B. Molecular Cytology of Microtubules; Springer: Berlin/Heidelberg, Germany, 1986; Volume 8, pp. 1–124. [Google Scholar]
- Shen, H.; Han, C.; Yang, Y.; Guo, L.; Sheng, Y.; Wang, J.; Li, W.; Zhai, L.; Wang, G.; Guan, Q. Pyroptosis executive protein GSDMD as a biomarker for diagnosis and identification of Alzheimer’s disease. Brain Behav. 2021, 11, e02063. [Google Scholar] [CrossRef] [PubMed]
- Gervais, F.G.; Xu, D.; Robertson, G.S.; Vaillancourt, J.P.; Zhu, Y.; Huang, J.; LeBlanc, A.; Smith, D.; Rigby, M.; Shearman, M.S.; et al. Involvement of caspases in proteolytic cleavage of Alzheimer’s amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell 1999, 97, 395–406. [Google Scholar] [CrossRef] [Green Version]
- Albrecht, S.; Bourdeau, M.; Bennett, D.; Mufson, E.J.; Bhattacharjee, M.; LeBlanc, A.C. Activation of caspase-6 in aging and mild cognitive impairment. Am. J. Pathol. 2007, 170, 1200–1209. [Google Scholar] [CrossRef] [Green Version]
- Ramcharitar, J.; Albrecht, S.; Afonso, V.M.; Kaushal, V.; Bennett, D.A.; Leblanc, A.C. Cerebrospinal fluid tau cleaved by caspase-6 reflects brain levels and cognition in aging and Alzheimer disease. J. Neuropathol. Exp. Neurol. 2013, 72, 824–832. [Google Scholar] [CrossRef]
- Zhang, X.; Zhu, C.; Beecham, G.; Vardarajan, B.N.; Ma, Y.; Lancour, D.; Farrell, J.J.; Chung, J.; Alzheimer’s Disease Sequencing, P.; Mayeux, R.; et al. A rare missense variant of CASP7 is associated with familial late-onset Alzheimer’s disease. Alzheimers Dement. 2019, 15, 441–452. [Google Scholar] [CrossRef]
- Rohn, T.T.; Head, E.; Nesse, W.H.; Cotman, C.W.; Cribbs, D.H. Activation of caspase-8 in the Alzheimer’s disease brain. Neurobiol. Dis. 2001, 8, 1006–1016. [Google Scholar] [CrossRef] [Green Version]
- Rehker, J.; Rodhe, J.; Nesbitt, R.R.; Boyle, E.A.; Martin, B.K.; Lord, J.; Karaca, I.; Naj, A.; Jessen, F.; Helisalmi, S.; et al. Caspase-8, association with Alzheimer’s Disease and functional analysis of rare variants. PLoS ONE 2017, 12, e0185777. [Google Scholar] [CrossRef] [Green Version]
- Rohn, T.T.; Rissman, R.A.; Davis, M.C.; Kim, Y.E.; Cotman, C.W.; Head, E. Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol. Dis. 2002, 11, 341–354. [Google Scholar] [CrossRef] [Green Version]
- Caccamo, A.; Branca, C.; Piras, I.S.; Ferreira, E.; Huentelman, M.J.; Liang, W.S.; Readhead, B.; Dudley, J.T.; Spangenberg, E.E.; Green, K.N.; et al. Necroptosis activation in Alzheimer’s disease. Nat. Neurosci. 2017, 20, 1236–1246. [Google Scholar] [CrossRef] [PubMed]
- Kischkel, F.C.; Hellbardt, S.; Behrmann, I.; Germer, M.; Pawlita, M.; Krammer, P.H.; Peter, M.E. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 1995, 14, 5579–5588. [Google Scholar] [CrossRef] [PubMed]
- Chinnaiyan, A.M.; O’Rourke, K.; Tewari, M.; Dixit, V.M. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995, 81, 505–512. [Google Scholar] [CrossRef] [Green Version]
- Slee, E.A.; Adrain, C.; Martin, S.J. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J. Biol. Chem. 2001, 276, 7320–7326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Slee, E.A.; Harte, M.T.; Kluck, R.M.; Wolf, B.B.; Casiano, C.A.; Newmeyer, D.D.; Wang, H.G.; Reed, J.C.; Nicholson, D.W.; Alnemri, E.S.; et al. Ordering the cytochrome c-initiated caspase cascade: Hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J. Cell Biol. 1999, 144, 281–292. [Google Scholar] [CrossRef] [PubMed]
- Li, P.; Nijhawan, D.; Budihardjo, I.; Srinivasula, S.M.; Ahmad, M.; Alnemri, E.S.; Wang, X. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997, 91, 479–489. [Google Scholar] [CrossRef] [Green Version]
- Zou, H.; Li, Y.; Liu, X.; Wang, X. An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 1999, 274, 11549–11556. [Google Scholar] [CrossRef] [Green Version]
- Callens, M.; Kraskovskaya, N.; Derevtsova, K.; Annaert, W.; Bultynck, G.; Bezprozvanny, I.; Vervliet, T. The role of Bcl-2 proteins in modulating neuronal Ca(2+) signaling in health and in Alzheimer’s disease. Biochim. Biophys. Acta Mol. Cell Res. 2021, 1868, 118997. [Google Scholar] [CrossRef]
- Kudo, W.; Lee, H.P.; Smith, M.A.; Zhu, X.; Matsuyama, S.; Lee, H.G. Inhibition of Bax protects neuronal cells from oligomeric Abeta neurotoxicity. Cell Death Dis. 2012, 3, e309. [Google Scholar] [CrossRef]
- Paradis, E.; Douillard, H.; Koutroumanis, M.; Goodyer, C.; LeBlanc, A. Amyloid beta peptide of Alzheimer’s disease downregulates Bcl-2 and upregulates bax expression in human neurons. J. Neurosci. 1996, 16, 7533–7539. [Google Scholar] [CrossRef] [Green Version]
- Drache, B.; Diehl, G.E.; Beyreuther, K.; Perlmutter, L.S.; Konig, G. Bcl-xl-specific antibody labels activated microglia associated with Alzheimer’s disease and other pathological states. J. Neurosci. Res. 1997, 47, 98–108. [Google Scholar] [CrossRef]
- Burguillos, M.A.; Deierborg, T.; Kavanagh, E.; Persson, A.; Hajji, N.; Garcia-Quintanilla, A.; Cano, J.; Brundin, P.; Englund, E.; Venero, J.L.; et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 2011, 472, 319–324. [Google Scholar] [CrossRef] [PubMed]
- Fricker, M.; Vilalta, A.; Tolkovsky, A.M.; Brown, G.C. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J. Biol. Chem. 2013, 288, 9145–9152. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stadelmann, C.; Deckwerth, T.L.; Srinivasan, A.; Bancher, C.; Bruck, W.; Jellinger, K.; Lassmann, H. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer’s disease. Evidence for apoptotic cell death. Am. J. Pathol. 1999, 155, 1459–1466. [Google Scholar] [CrossRef]
- Su, J.H.; Zhao, M.; Anderson, A.J.; Srinivasan, A.; Cotman, C.W. Activated caspase-3 expression in Alzheimer’s and aged control brain: Correlation with Alzheimer pathology. Brain Res. 2001, 898, 350–357. [Google Scholar] [CrossRef]
- Rohn, T.T.; Kokoulina, P.; Eaton, C.R.; Poon, W.W. Caspase activation in transgenic mice with Alzheimer-like pathology: Results from a pilot study utilizing the caspase inhibitor, Q-VD-OPh. Int. J. Clin. Exp. Med. 2009, 2, 300–308. [Google Scholar]
- Biscaro, B.; Lindvall, O.; Tesco, G.; Ekdahl, C.T.; Nitsch, R.M. Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer’s disease. Neurodegener Dis. 2012, 9, 187–198. [Google Scholar] [CrossRef] [Green Version]
- Grootjans, S.; Vanden Berghe, T.; Vandenabeele, P. Initiation and execution mechanisms of necroptosis: An overview. Cell Death Differ. 2017, 24, 1184–1195. [Google Scholar] [CrossRef]
- Dondelinger, Y.; Declercq, W.; Montessuit, S.; Roelandt, R.; Goncalves, A.; Bruggeman, I.; Hulpiau, P.; Weber, K.; Sehon, C.A.; Marquis, R.W.; et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 2014, 7, 971–981. [Google Scholar] [CrossRef] [Green Version]
- Wang, H.; Sun, L.; Su, L.; Rizo, J.; Liu, L.; Wang, L.F.; Wang, F.S.; Wang, X. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 2014, 54, 133–146. [Google Scholar] [CrossRef] [Green Version]
- Feng, S.; Yang, Y.; Mei, Y.; Ma, L.; Zhu, D.E.; Hoti, N.; Castanares, M.; Wu, M. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell. Signal. 2007, 19, 2056–2067. [Google Scholar] [CrossRef] [PubMed]
- Degterev, A.; Hitomi, J.; Germscheid, M.; Ch’en, I.L.; Korkina, O.; Teng, X.; Abbott, D.; Cuny, G.D.; Yuan, C.; Wagner, G.; et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008, 4, 313–321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cho, Y.S.; Challa, S.; Moquin, D.; Genga, R.; Ray, T.D.; Guildford, M.; Chan, F.K. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 2009, 137, 1112–1123. [Google Scholar] [CrossRef] [Green Version]
- He, S.; Wang, L.; Miao, L.; Wang, T.; Du, F.; Zhao, L.; Wang, X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009, 137, 1100–1111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, D.W.; Shao, J.; Lin, J.; Zhang, N.; Lu, B.J.; Lin, S.C.; Dong, M.Q.; Han, J. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 2009, 325, 332–336. [Google Scholar] [CrossRef] [PubMed]
- Sun, L.; Wang, H.; Wang, Z.; He, S.; Chen, S.; Liao, D.; Wang, L.; Yan, J.; Liu, W.; Lei, X.; et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 2012, 148, 213–227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhao, J.; Jitkaew, S.; Cai, Z.; Choksi, S.; Li, Q.; Luo, J.; Liu, Z.G. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl. Acad. Sci. USA 2012, 109, 5322–5327. [Google Scholar] [CrossRef] [Green Version]
- Ofengeim, D.; Mazzitelli, S.; Ito, Y.; DeWitt, J.P.; Mifflin, L.; Zou, C.; Das, S.; Adiconis, X.; Chen, H.; Zhu, H.; et al. RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 2017, 114, E8788–E8797. [Google Scholar] [CrossRef] [Green Version]
- Chung, S.H. Aberrant phosphorylation in the pathogenesis of Alzheimer’s disease. BMB Rep. 2009, 42, 467–474. [Google Scholar] [CrossRef] [Green Version]
- Rogers, C.; Fernandes-Alnemri, T.; Mayes, L.; Alnemri, D.; Cingolani, G.; Alnemri, E.S. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 2017, 8, 14128. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Gao, W.; Shi, X.; Ding, J.; Liu, W.; He, H.; Wang, K.; Shao, F. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 2017, 547, 99–103. [Google Scholar] [CrossRef] [PubMed]
- Rogers, C.; Erkes, D.A.; Nardone, A.; Aplin, A.E.; Fernandes-Alnemri, T.; Alnemri, E.S. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 2019, 10, 1689. [Google Scholar] [CrossRef] [PubMed]
- Orning, P.; Weng, D.; Starheim, K.; Ratner, D.; Best, Z.; Lee, B.; Brooks, A.; Xia, S.; Wu, H.; Kelliher, M.A.; et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 2018, 362, 1064–1069. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sarhan, J.; Liu, B.C.; Muendlein, H.I.; Li, P.; Nilson, R.; Tang, A.Y.; Rongvaux, A.; Bunnell, S.C.; Shao, F.; Green, D.R.; et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl. Acad. Sci. USA 2018, 115, E10888–E10897. [Google Scholar] [CrossRef] [Green Version]
- Pompl, P.N.; Yemul, S.; Xiang, Z.; Ho, L.; Haroutunian, V.; Purohit, D.; Mohs, R.; Pasinetti, G.M. Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch. Neurol. 2003, 60, 369–376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kesavardhana, S.; Kanneganti, T.D. ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease. J. Exp. Med. 2020, 217. [Google Scholar] [CrossRef] [PubMed]
- Malireddi, R.K.S.; Tweedell, R.E.; Kanneganti, T.D. PANoptosis components, regulation, and implications. Aging 2020, 12, 11163–11164. [Google Scholar] [CrossRef] [PubMed]
- Place, D.E.; Lee, S.; Kanneganti, T.D. PANoptosis in microbial infection. Curr. Opin. Microbiol. 2021, 59, 42–49. [Google Scholar] [CrossRef] [PubMed]
- Dunn, N.; Mullee, M.; Perry, V.H.; Holmes, C. Association between dementia and infectious disease: Evidence from a case-control study. Alzheimer Dis. Assoc. Disord. 2005, 19, 91–94. [Google Scholar] [CrossRef] [PubMed]
- Coperchini, F.; Chiovato, L.; Croce, L.; Magri, F.; Rotondi, M. The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system. Cytokine Growth Factor Rev. 2020, 53, 25–32. [Google Scholar] [CrossRef] [PubMed]
- Serrano-Castro, P.J.; Estivill-Torrus, G.; Cabezudo-Garcia, P.; Reyes-Bueno, J.A.; Ciano Petersen, N.; Aguilar-Castillo, M.J.; Suarez-Perez, J.; Jimenez-Hernandez, M.D.; Moya-Molina, M.A.; Oliver-Martos, B.; et al. Impact of SARS-CoV-2 infection on neurodegenerative and neuropsychiatric diseases: A delayed pandemic? Neurología 2020, 35, 245–251. [Google Scholar] [CrossRef] [PubMed]
- Karki, R.; Kanneganti, T.D. The ‘cytokine storm’: Molecular mechanisms and therapeutic prospects. Trends Immunol. 2021, 42, 681–705. [Google Scholar] [CrossRef] [PubMed]
- Patel, N.S.; Paris, D.; Mathura, V.; Quadros, A.N.; Crawford, F.C.; Mullan, M.J. Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer’s disease. J. Neuroinflammation 2005, 2, 9. [Google Scholar] [CrossRef] [Green Version]
- Minter, M.R.; Taylor, J.M.; Crack, P.J. The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem. 2016, 136, 457–474. [Google Scholar] [CrossRef] [PubMed]
- Hu, W.T.; Howell, J.C.; Ozturk, T.; Gangishetti, U.; Kollhoff, A.L.; Hatcher-Martin, J.M.; Anderson, A.M.; Tyor, W.R. CSF Cytokines in Aging, Multiple Sclerosis, and Dementia. Front. Immunol. 2019, 10, 480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Genazzani, A.D.; Forti, G.; Guardabasso, V.; Maggi, M.; Milloni, M.; Cianfanelli, F.; Serio, M. Frequency of prolactin pulsatile release in normal men and in agonadal patients is neither coupled to LH release nor influenced by androgen modulation. Clin. Endocrinol. 1992, 37, 65–71. [Google Scholar] [CrossRef] [PubMed]
- Vom Berg, J.; Prokop, S.; Miller, K.R.; Obst, J.; Kalin, R.E.; Lopategui-Cabezas, I.; Wegner, A.; Mair, F.; Schipke, C.G.; Peters, O.; et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 2012, 18, 1812–1819. [Google Scholar] [CrossRef]
- Rentzos, M.; Paraskevas, G.P.; Kapaki, E.; Nikolaou, C.; Zoga, M.; Rombos, A.; Tsoutsou, A.; Vassilopoulos, D.D. Interleukin-12 is reduced in cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. J. Neurol. Sci. 2006, 249, 110–114. [Google Scholar] [CrossRef]
- Decourt, B.; Lahiri, D.K.; Sabbagh, M.N. Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease. Curr Alzheimer Res. 2017, 14, 412–425. [Google Scholar] [CrossRef] [Green Version]
- Meda, L.; Cassatella, M.A.; Szendrei, G.I.; Otvos, L., Jr.; Baron, P.; Villalba, M.; Ferrari, D.; Rossi, F. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995, 374, 647–650. [Google Scholar] [CrossRef]
- Tan, J.; Town, T.; Paris, D.; Mori, T.; Suo, Z.; Crawford, F.; Mattson, M.P.; Flavell, R.A.; Mullan, M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 1999, 286, 2352–2355. [Google Scholar] [CrossRef] [PubMed]
- Tan, J.; Town, T.; Crawford, F.; Mori, T.; DelleDonne, A.; Crescentini, R.; Obregon, D.; Flavell, R.A.; Mullan, M.J. Role of CD40 ligand in amyloidosis in transgenic Alzheimer’s mice. Nat. Neurosci. 2002, 5, 1288–1293. [Google Scholar] [CrossRef] [PubMed]
- Chakrabarty, P.; Ceballos-Diaz, C.; Beccard, A.; Janus, C.; Dickson, D.; Golde, T.E.; Das, P. IFN-gamma promotes complement expression and attenuates amyloid plaque deposition in amyloid beta precursor protein transgenic mice. J. Immunol. 2010, 184, 5333–5343. [Google Scholar] [CrossRef] [PubMed]
- Lue, L.F.; Rydel, R.; Brigham, E.F.; Yang, L.B.; Hampel, H.; Murphy, G.M., Jr.; Brachova, L.; Yan, S.D.; Walker, D.G.; Shen, Y.; et al. Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia 2001, 35, 72–79. [Google Scholar] [CrossRef] [PubMed]
- Laske, C.; Stransky, E.; Hoffmann, N.; Maetzler, W.; Straten, G.; Eschweiler, G.W.; Leyhe, T. Macrophage colony-stimulating factor (M-CSF) in plasma and CSF of patients with mild cognitive impairment and Alzheimer’s disease. Curr. Alzheimer Res. 2010, 7, 409–414. [Google Scholar] [CrossRef] [PubMed]
- Hirsch-Reinshagen, V.; Maia, L.F.; Burgess, B.L.; Blain, J.F.; Naus, K.E.; McIsaac, S.A.; Parkinson, P.F.; Chan, J.Y.; Tansley, G.H.; Hayden, M.R.; et al. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J. Biol. Chem. 2005, 280, 43243–43256. [Google Scholar] [CrossRef] [Green Version]
- Akama, K.T.; Van Eldik, L.J. Beta-amyloid stimulation of inducible nitric-oxide synthase in astrocytes is interleukin-1beta- and tumor necrosis factor-alpha (TNFalpha)-dependent, and involves a TNFalpha receptor-associated factor- and NFkappaB-inducing kinase-dependent signaling mechanism. J. Biol. Chem. 2000, 275, 7918–7924. [Google Scholar] [CrossRef] [Green Version]
- Shaftel, S.S.; Carlson, T.J.; Olschowka, J.A.; Kyrkanides, S.; Matousek, S.B.; O’Banion, M.K. Chronic interleukin-1beta expression in mouse brain leads to leukocyte infiltration and neutrophil-independent blood brain barrier permeability without overt neurodegeneration. J. Neurosci. 2007, 27, 9301–9309. [Google Scholar] [CrossRef]
- Ghosh, S.; Wu, M.D.; Shaftel, S.S.; Kyrkanides, S.; LaFerla, F.M.; Olschowka, J.A.; O’Banion, M.K. Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer’s mouse model. J. Neurosci. 2013, 33, 5053–5064. [Google Scholar] [CrossRef]
- Tarkowski, E.; Andreasen, N.; Tarkowski, A.; Blennow, K. Intrathecal inflammation precedes development of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 2003, 74, 1200–1205. [Google Scholar] [CrossRef]
- Jin, J.J.; Kim, H.D.; Maxwell, J.A.; Li, L.; Fukuchi, K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J. Neuroinflammation 2008, 5, 23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Savarin-Vuaillat, C.; Ransohoff, R.M. Chemokines and chemokine receptors in neurological disease: Raise, retain, or reduce? Neurotherapeutics 2007, 4, 590–601. [Google Scholar] [CrossRef] [PubMed]
- Xia, M.Q.; Qin, S.X.; Wu, L.J.; Mackay, C.R.; Hyman, B.T. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains. Am. J. Pathol. 1998, 153, 31–37. [Google Scholar] [CrossRef]
- Ishizuka, K.; Kimura, T.; Igata-yi, R.; Katsuragi, S.; Takamatsu, J.; Miyakawa, T. Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin. Neurosci. 1997, 51, 135–138. [Google Scholar] [CrossRef]
- Smits, H.A.; Rijsmus, A.; van Loon, J.H.; Wat, J.W.; Verhoef, J.; Boven, L.A.; Nottet, H.S. Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J. Neuroimmunol. 2002, 127, 160–168. [Google Scholar] [CrossRef]
- Lue, L.F.; Walker, D.G.; Rogers, J. Modeling microglial activation in Alzheimer’s disease with human postmortem microglial cultures. Neurobiol. Aging 2001, 22, 945–956. [Google Scholar] [CrossRef]
- Fuhrmann, M.; Bittner, T.; Jung, C.K.; Burgold, S.; Page, R.M.; Mitteregger, G.; Haass, C.; LaFerla, F.M.; Kretzschmar, H.; Herms, J. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat. Neurosci. 2010, 13, 411–413. [Google Scholar] [CrossRef] [Green Version]
- Lee, S.; Varvel, N.H.; Konerth, M.E.; Xu, G.; Cardona, A.E.; Ransohoff, R.M.; Lamb, B.T. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am. J. Pathol. 2010, 177, 2549–2562. [Google Scholar] [CrossRef]
- Cho, S.H.; Sun, B.; Zhou, Y.; Kauppinen, T.M.; Halabisky, B.; Wes, P.; Ransohoff, R.M.; Gan, L. CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease. J. Biol. Chem. 2011, 286, 32713–32722. [Google Scholar] [CrossRef] [Green Version]
- Holmes, C.; Boche, D.; Wilkinson, D.; Yadegarfar, G.; Hopkins, V.; Bayer, A.; Jones, R.W.; Bullock, R.; Love, S.; Neal, J.W.; et al. Long-term effects of Abeta42 immunisation in Alzheimer’s disease: Follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008, 372, 216–223. [Google Scholar] [CrossRef] [Green Version]
- Rabinovici, G.D. Controversy and Progress in Alzheimer’s Disease—FDA Approval of Aducanumab. N. Engl. J. Med. 2021, 385, 771–774. [Google Scholar] [CrossRef] [PubMed]
- Budd-Haeberlein, S.; Von Hein, C.; Tian, Y.; Chalkias, S.; Muralidharan, K.K.; Chen, T.; Wu, S.; Skordos, L.; Nisenbaum, L.; Rajagovindan, R.; et al. EMERGE and ENGAGE topline results: Two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. In Proceedings of the Advances in Alzheimer’s and Parkinson’s Therapies: An AAT-AD/PD Focus Meeting, Vienna, Austria, 2–5 April 2020. [Google Scholar]
- Congdon, E.E.; Sigurdsson, E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2018, 14, 399–415. [Google Scholar] [CrossRef] [PubMed]
- Bittar, A.; Bhatt, N.; Kayed, R. Advances and considerations in AD tau-targeted immunotherapy. Neurobiol. Dis. 2020, 134, 104707. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.S.; Suh, Y.H. Minocycline and neurodegenerative diseases. Behav. Brain Res. 2009, 196, 168–179. [Google Scholar] [CrossRef] [PubMed]
- Howard, R.; Zubko, O.; Gray, R.; Bradley, R.; Harper, E.; Kelly, L.; Pank, L.; O’Brien, J.; Fox, C.; Tabet, N.; et al. Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer’s disease: The MADE Phase II, three-arm RCT. Effic. Mech. Eval. 2020, 7, 1–45. [Google Scholar] [CrossRef] [PubMed]
- Mangan, M.S.J.; Olhava, E.J.; Roush, W.R.; Seidel, H.M.; Glick, G.D.; Latz, E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 2018, 17, 588–606. [Google Scholar] [CrossRef] [PubMed]
- Primiano, M.J.; Lefker, B.A.; Bowman, M.R.; Bree, A.G.; Hubeau, C.; Bonin, P.D.; Mangan, M.; Dower, K.; Monks, B.G.; Cushing, L.; et al. Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation. J. Immunol. 2016, 197, 2421–2433. [Google Scholar] [CrossRef] [Green Version]
- Esmaeili, M.H.; Enayati, M.; Khabbaz Abkenar, F.; Ebrahimian, F.; Salari, A.A. Glibenclamide mitigates cognitive impairment and hippocampal neuroinflammation in rats with type 2 diabetes and sporadic Alzheimer-like disease. Behav. Brain Res. 2020, 379, 112359. [Google Scholar] [CrossRef]
- Flores, J.; Noel, A.; Foveau, B.; Lynham, J.; Lecrux, C.; LeBlanc, A.C. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model. Nat. Commun. 2018, 9, 3916. [Google Scholar] [CrossRef] [Green Version]
- Mandrioli, J.; D’Amico, R.; Zucchi, E.; Gessani, A.; Fini, N.; Fasano, A.; Caponnetto, C.; Chio, A.; Dalla Bella, E.; Lunetta, C.; et al. Rapamycin treatment for amyotrophic lateral sclerosis: Protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine 2018, 97, e11119. [Google Scholar] [CrossRef]
- Wang, S.; Mustafa, M.; Yuede, C.M.; Salazar, S.V.; Kong, P.; Long, H.; Ward, M.; Siddiqui, O.; Paul, R.; Gilfillan, S.; et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 2020, 217. [Google Scholar] [CrossRef] [PubMed]
- Brazier, D.; Perry, R.; Keane, J.; Barrett, K.; Elmaleh, D.R. Pharmacokinetics of Cromolyn and Ibuprofen in Healthy Elderly Volunteers. Clin. Drug Investig. 2017, 37, 1025–1034. [Google Scholar] [CrossRef] [PubMed]
- Zhang, C.; Griciuc, A.; Hudry, E.; Wan, Y.; Quinti, L.; Ward, J.; Forte, A.M.; Shen, X.; Ran, C.; Elmaleh, D.R.; et al. Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid beta-Protein by Promoting Microglial Phagocytosis. Sci. Rep. 2018, 8, 1144. [Google Scholar] [CrossRef] [PubMed]
- Blacher, E.; Dadali, T.; Bespalko, A.; Haupenthal, V.J.; Grimm, M.O.; Hartmann, T.; Lund, F.E.; Stein, R.; Levy, A. Alzheimer’s disease pathology is attenuated in a CD38-deficient mouse model. Ann. Neurol. 2015, 78, 88–103. [Google Scholar] [CrossRef] [PubMed]
- Guerreiro, S.; Privat, A.L.; Bressac, L.; Toulorge, D. CD38 in Neurodegeneration and Neuroinflammation. Cells 2020, 9, 471. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lai, J.; Mei, Z.L.; Wang, H.; Hu, M.; Long, Y.; Miao, M.X.; Li, N.; Hong, H. Montelukast rescues primary neurons against Abeta1-42-induced toxicity through inhibiting CysLT1R-mediated NF-kappaB signaling. Neurochem. Int. 2014, 75, 26–31. [Google Scholar] [CrossRef]
- Morin, N.; Jourdain, V.A.; Morissette, M.; Gregoire, L.; Di Paolo, T. Long-term treatment with l-DOPA and an mGlu5 receptor antagonist prevents changes in brain basal ganglia dopamine receptors, their associated signaling proteins and neuropeptides in parkinsonian monkeys. Neuropharmacology 2014, 79, 688–706. [Google Scholar] [CrossRef]
- Estus, S.; Shaw, B.C.; Devanney, N.; Katsumata, Y.; Press, E.E.; Fardo, D.W. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol. 2019, 138, 187–199. [Google Scholar] [CrossRef]
- Friker, L.L.; Scheiblich, H.; Hochheiser, I.V.; Brinkschulte, R.; Riedel, D.; Latz, E.; Geyer, M.; Heneka, M.T. beta-Amyloid Clustering around ASC Fibrils Boosts Its Toxicity in Microglia. Cell Rep. 2020, 30, 3743–3754.e6. [Google Scholar] [CrossRef]
- Salter, M.W.; Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 2017, 23, 1018–1027. [Google Scholar] [CrossRef]
- Marsh, S.E.; Abud, E.M.; Lakatos, A.; Karimzadeh, A.; Yeung, S.T.; Davtyan, H.; Fote, G.M.; Lau, L.; Weinger, J.G.; Lane, T.E.; et al. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl. Acad. Sci. USA 2016, 113, E1316–E1325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Da Mesquita, S.; Louveau, A.; Vaccari, A.; Smirnov, I.; Cornelison, R.C.; Kingsmore, K.M.; Contarino, C.; Onengut-Gumuscu, S.; Farber, E.; Raper, D.; et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 2018, 560, 185–191. [Google Scholar] [CrossRef] [PubMed]
- Olate-Briones, A.; Escalona, E.; Salazar, C.; Herrada, M.J.; Liu, C.; Herrada, A.A.; Escobedo, N. The meningeal lymphatic vasculature in neuroinflammation. FASEB J. 2022, 36, e22276. [Google Scholar] [CrossRef] [PubMed]
- Da Mesquita, S.; Papadopoulos, Z.; Dykstra, T.; Brase, L.; Farias, F.G.; Wall, M.; Jiang, H.; Kodira, C.D.; de Lima, K.A.; Herz, J.; et al. Meningeal lymphatics affect microglia responses and anti-Abeta immunotherapy. Nature 2021, 593, 255–260. [Google Scholar] [CrossRef]
- Zou, W.; Pu, T.; Feng, W.; Lu, M.; Zheng, Y.; Du, R.; Xiao, M.; Hu, G. Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated alpha-synuclein. Transl. Neurodegener 2019, 8, 7. [Google Scholar] [CrossRef]
Gene | Category | Lead Variant | Cell Type | Role in AD Pathogenesis | Reference |
---|---|---|---|---|---|
TREM2 | Immune receptor | rs187370608 | Microglia | Negatively impacts binding to cell-surface TREM2 ligands and Aβ oligomers | [57,81,82,83,84,85] |
TREM2 R47H | Late onset of AD | ||||
T96K | Gain-of-function mutation, resulting in increased cellular binding | ||||
CD33 | Immune receptor | Minor allele of CD33 SNP rs3865444 | Microglia | Confers protection against AD; reduced levels of full-length CD33 and insoluble Aβ42 | |
INPP5D | Signaling intermediate | Intron variant rs10933431 | Microglia | − | |
CLU | Complement | Intron Variant rs4236673 | Astrocyte | Aβ clearance | |
CR1 | Complement | Intron variant rs2093760 | Microglia | Aβ clearance | |
SPI1 | Transcription factor | − | Microglia | Aβ clearance | |
ABCA7 | − | Neuron | Aβ clearance | ||
Microglia | APP processing | ||||
EPHA1 | Effector mechanism | Intron variant rs7810606 | Oligodendrocyte | Tau pathology | |
Microglia | |||||
MS4As | Immune receptor | Intergenic rs2081545 | Microglia | − | |
HLA-DRB5-DRB1 | Immune receptor | Intergenic rs6931277 | Microglia receptor | − | |
CASP7 | Cell death | Missense variant Gene wise | − | − | |
CASP8 | Cell death | Missense variant Gene wise | Neurons | Amyloid processing |
Sensors | Model System | Cell Type | Mechanism | Role in AD Pathogenesis | Reference |
---|---|---|---|---|---|
TLRs | |||||
TLR2 | APP/PS1 mouse model | Microglia | TLR2 deficiency in microglia induces expression of TNF-α, IL-1β, IL-8, and enhanced Aβ clearance | High extracellular Aβ deposits; impairs cognitive function | [77,79,80] |
Inhibition of TLR2 activity attenuates glial cell reactivity and leads to reduction in Aβ deposits | |||||
TLR4 | APP/PS1 mouse model | Microglia | TLR4 deficiency reduces microglial activation, and its activation in microglia enhances production of Aβ peptides | Alteration in extracellular Aβ deposits | [71,86] |
AD samples | Increased amounts of inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-8 | Impairs cognitive function | |||
TLR9 | Tg2576 mouse model | Neurons | TLR9 agonist (CpG oligonucleotides) induces reduction of cortical and vascular Aβ levels | Improves cognitive function | [84] |
3xTg AD mouse model | TLR9 agonist (CpG ODN) reduces amyloid burden and Tau-related pathology | Reduces amyloid plaque and NFT pathology; cognitive benefit | |||
Inflammasome sensors | |||||
NLRP1 | Human neurons | Neurons | Link between intraneuronal inflammasome activation, CASP1 activation, and IL-1β-mediated neuroinflammation and CASP6-mediated axonal degeneration | Neuroinflammation, axonal degeneration, and cognitive impairment | [87] |
NLRP3 | Human and mouse brain tissue samples | Microglia and neurons | Mutations associated with familial AD in Nlrp3−/− or Casp1−/− models showed protection from AD-associated loss of spatial memory and other sequelae | Inflammation, behavioral, and cognitive dysfunction | [88] |
APP/PS1 mouse model | NLRP3 deficiency aligned microglial cells to an M2 phenotype, leading to reduced deposition of Aβ | Elevated brain CASP1 and IL-1β activation, reduced Aβ deposition | |||
NLRC4 | Mouse model (C57BL/6 Nlrc4−/−) | Microglia and astrocytes | LPC induces NLRP3- and NLRC4-dependent inflammasome activation | Astrogliosis, microglial accumulation, alteration in expression of LPC receptor G2A | [89] |
High expression of NLRC4 in mice astrocytes and human demyelinating-associated disease neurological samples | |||||
AIM2 | 5xFAD mouse model | Microglia | Aim2 knockout reduces Aβ deposition and microglial activation; no beneficial effect on spatial memory or cytokine expression | Increase in Aβ deposition and microglial activation | [90] |
Other cell surface receptors | |||||
TREM2 | 5xFAD mouse model | Microglia | TREM2 deficiency enhances Aβ accumulation and neuronal loss | Neurodegeneration | [91] |
plaques and senses anionic lipids interacting with fibrillar Aβ | |||||
APP/PS1-21 mouse model | TREM2 R47H mutation worsens lipid recognition in AD | Sustaining microglia in response to Aβ accumulation | |||
Adaptors | |||||
ASC | Mouse model (C57BL/6 Asc−/−) | Microglia and astrocytes | Involvement of ASC, CASP1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux in LPC-mediated inflammasome activation | Astrogliosis and microglial accumulation | [89] |
MAVS | Agt5fl/flCd11bCre mouse model | Microglia | MAVS signaling mediates poly(I:C)-induced inflammation in the brain | Prevents MPTP-induced microglial activation and dopaminergic neuron loss | [92] |
Autophagy negatively regulates the activity of MAVS through direct binding of LC3 to the LIR motif Y(9)xxI(12) of MAVS | |||||
Other cytosolic sensors | |||||
cGAS-STING | AD patient samples | Microglia | Higher protein levels of STING when compared to control patients; increased phosphorylation of IRF3 | Activated pathway affects microglial function | [93] |
Decreased Aβ fibril phagocytosis upon STING’s activation | |||||
RIG-I | AD patient samples | Astrocytes | Stimulation with RIG-I increased expression of APP and Aβ | Involved in the pathology of MCI associated with early progression to AD | [94] |
Effectors | Model System | Cell Type | Mechanism | Role in AD Pathogenesis | Reference |
---|---|---|---|---|---|
GSDMD | Mice | Neurons | Aβ1-42 induces pyroptosis through GSDMD and NLRP3-CASP1 signaling-mediated GSDMD cleavage | Nerve injury and neuronal loss | [142,145] |
NLRP3/CASP1/GSDMD axis induces neuronal pyroptosis | Increased inflammatory factors (IL-1β and IL-6) in CSF | [146] | |||
CASP3 | Human and mouse samples | Neurons | CASP3-mediated CASP8, CASP9, and CASP10 processing drive amyloid precursor protein cleavage | Neuronal death and plaque formation | [147] |
CASP6 | AD patient’s CSF samples | NFT | CSF samples indicate TauΔCasp6 level and CASP6 immunoreactivity | Cognitive impairment | [148,149] |
Levels of CSF TauΔCasp6 are inversely correlated with cognitive scores | Tau cleavage | ||||
CASP7 | Whole genome sequence data of human samples | ADAM10, BACE, and PSEN1/2 secretases process APP | Familial late-onset AD associated with a CASP7 missense variant | [150] | |
Alternative processing of APP results in cleavage of C31 fragment through CASP7 | |||||
CASP8 | Autopsy of brain tissue from hippocampus and entorhinal cortex | Neurons | Activation of apoptotic programs in neurons of AD brain activates death receptor pathway and CASP8 | Amyloid processing, synaptic plasticity, learning/memory, controls microglia, proinflammatory activation, and neurotoxicity | [151,152] |
Aβ mediates apoptosis in neurons via Fas/TNF family of death receptors, followed by activation of CASP8 and CASP3 | |||||
CASP9 | Rat PC12 cells; human samples | Neurons | Colocalization of active CASP9 with active CASP8 and accumulation of CASP3-cleavage products of fodrin | Activation in Tau cleavage | [153] |
Activation of CASP9 in neurons positive for oxidative damage to DNA/RNA | |||||
CASP9 activation leads to NFT formation | |||||
RIPK1 | Human and rat | Neurons (temporal gyrus tissue) | RIPK1-mediated necroptosis in neuronal cells involves the mTORC1 pathway | Gene expression dysregulations in AD are predicted by RIPK1 | [154] |
MLKL | Human and mice | Neurons (temporal gyrus tissue) | High pMLKL levels and MLKL dimers in AD brains and colocalization of pMLKL with membrane marker cadherin; pMLKL immunoreactivity localized to membrane | Necrosome formation | [154] |
Molecules | Model System | Cell Type | Mechanism | Role in AD Pathogenesis | Reference |
---|---|---|---|---|---|
Inflammasome-associated inflammatory cytokines | |||||
IL-1α | TgAPPsw and PSAPP transgenic mice | Brain slices | Increased Aβ | Accumulation of Aβ drives neuroinflammatory responses | [196] |
IL-1β | In vitro | Microglia | Microglial activation by Aβ | Recruit microglia and astrocytes to Aβ locus | [197] |
IL-18 | AD samples | CSF | TNF-α, IP-10, and IL-18 levels increase linearly with age | Age-related shift from Th1- to non-Th1–related cytokines | [198] |
Pleotropic cytokines | |||||
IL-10 | AD samples | CSF | IL-10 correlated with age in a U-shaped relationship | AD accelerates the shift away from Th1 phenotypes | [198] |
Other inflammatory cytokines | |||||
IL-6 | − | Microglia | Microglial activation by Aβ | Recruit microglia and astrocytes to Aβ locus | [197] |
TgAPPsw and PSAPP transgenic mice | Brain slices | Increased Aβ | Accumulation of Aβ drives neuroinflammatory responses | [196] | |
In vitro | Microglia | Pre-aggregated Aβ1-42 exposure to microglia | Increased production of proinflammatory cytokines | [199] | |
IL-12 | AD samples and mouse model (SAMP8, APP/PS1) | Microglia | IL-12 inhibition improves AD-like pathology | Ameliorates AD-associated neuropathology and spacial memory; cognitive decline | [143,200,201] |
IL-23 | AD samples and mouse model (SAMP8, APP/PS1) | Microglia | IL-23 inhibition improves AD-like pathology | Ameliorates AD-associated neuropathology and spacial memory; cognitive decline | [143,200,201] |
TNF-α | AD samples | Neurons | Phase I and IIa clinical trial of TNF-α inhibitors reduces cognitive decline and improves daily activities | Exacerbates Aβ and Tau pathologies | [202] |
− | Microglia | Aβ activates microglia | Recruit microglia and astrocytes to Aβ locus | [197] | |
TgAPPsw and PSAPP transgenic mice | Brain slices | Higher levels of Aβ | Accumulation of Aβ drives neuroinflammatory responses | [196] | |
In vitro | Microglia | In response to pre-aggregated Aβ1-42 treatment, microglia release TNF-α | Increased production of proinflammatory cytokines | [199] | |
Interferons | |||||
IFN-γ | − | Neuron, microglia co-culture | Synergistic action of Aβ with IFN-γ or CD40 ligand triggers TNF-α secretion | Production of neurotoxic ROS | [203,204,205] |
TgCRND8 mouse model | AAV-mediated expression of IFN-γ in the brains | Enhanced amyloid plaque clearance; increased astrogliosis and microgliosis; reduced levels of soluble Aβ and Aβ plaque burden | [206] | ||
Chemokines | |||||
MIP-1α | In vitro | Microglia | Pre-aggregated Aβ1-42 exposure to microglia | Increased production of proinflammatory cytokines | [207] |
M-CSF | In vitro | Microglia | Pre-aggregated Aβ1-42 exposure to microglia | Increased production of proinflammatory cytokines | [207,208,209] |
AD samples | Plasma samples | High M-CSF levels | Mild cognitive impairment | ||
GM-CSF | TgAPPsw and PSAPP transgenic mice | Brain slices | Increased Aβ | Accumulation of Aβ drives neuroinflammatory responses | [196] |
Target | Therapy/Drug | Mechanism of Action | Impact on AD | Clinical Phase | Reference |
---|---|---|---|---|---|
NLRP3 | CP-456,733 (CRID/MCC950) | Diarylsulfonylurea compound specifically inhibits NLRP3 inflammasome | Promotes microglial Aβ clearance; reduces Aβ accumulation; improves cognitive function | Moving to Phase II | [38,125,230,231] |
Reduces cellular release of IL-1β, IL-1α, and IL-18 | |||||
Glyburide | Sulfonylurea-based compound inhibiting NLRP3 inflammasome activation | Mitigates cognitive impairment | − | [230,232] | |
Reduces hippocampal neuroinflammation | |||||
CASP1 | VX-765 | Inhibits CASP1, reduces IL-1β/IL-18 release | Prevents progressive Aβ deposition and reverses brain inflammation | − | [38,233] |
Normalizes synaptophysin protein levels | |||||
GSDMD | Disulfiram + Bay 11-7082 | Inhibits GSDMD-mediated pyroptosis by covalent modification of 191/192 cysteine residue of GSDMD | − | − | |
RIPK1 | DNL747 | RIPK1 inhibitor | − | Phase I | [234] |
RAGE | Azeliragon | Reduces inflammation | Reduces Aβ transport to brain | Phase III | [207] |
Diminishes toxic effects of oligomers | |||||
TREM2 | AL002 | Targets microglial TREM2 receptors | Promotes microglial clearance of Aβ and reduces neurotoxicity | Phase II | [235] |
Neuro-inflammation | ALZT-OP1 (cromolyn + ibuprofen) | − | Reduces Aβ aggregation. | Phase II | [236,237] |
Induces neuroprotective microglial activation | |||||
Daratumumab | Targets CD38 on glia cells | Regulates microglial activity | Phase II | [238,239] | |
Montelukast | CysLT-1 receptor antagonist | Affects inflammatory processes, neuronal injury, BBB integrity, and Aβ protein accumulation | Phase II | [240,241] | |
AL003 | Targets SIGLEC-3 (CD33) | Reactivates microglia and brain immune cells | Phase I | [242] | |
Aids microglial clearance of toxic proteins | |||||
TNF-α | Adalimumab | Humanized anti-TNF-α antibody | Attenuates neuronal damage and neuroinflammation | Preclinical [125] | |
Decreases beta secretase-1 protein expression and Aβ1-40 plaques; improves cognitive functions | |||||
XPro1595 | Targets only soluble form of TNF-α | Reduces pre-plaque Aβ pathology and microglia activation | Preclinical [125] | ||
Improves synaptic and cognitive functions | |||||
IL-12/IL-23 | Genetic ablation or pharmacological manipulation | Genetic ablation of IL-12/IL-23 signaling molecules p40, p35, or p19 | Reduces cerebral Aβ load | Preclinical [125] | |
Reduces cognitive deficit |
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Rajesh, Y.; Kanneganti, T.-D. Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease. Cells 2022, 11, 1885. https://doi.org/10.3390/cells11121885
Rajesh Y, Kanneganti T-D. Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease. Cells. 2022; 11(12):1885. https://doi.org/10.3390/cells11121885
Chicago/Turabian StyleRajesh, Yetirajam, and Thirumala-Devi Kanneganti. 2022. "Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease" Cells 11, no. 12: 1885. https://doi.org/10.3390/cells11121885