Review Article

Role of Neuroinflammation in Alzheimer’s Disease (AD)

Abstract

Neuroinflammation is a critical process in Alzheimer’s disease (AD) development in which different types of cells and cytokines are involved. Proinflammatory cytokine production and the disturbance of anti-inflammatory pathways play critical roles in AD. Neuroinflammation is affected by various factors such as metabolism (metabolic diseases such as obesity), genetics, and immune cells especially resident immune cells in the brain. Moreover, main pro-inflammatory cytokines and inflammatory pathways have different effects on neuroinflammation, neuronal biogenesis, and neuronal apoptosis in AD. Exploration of the relationship between neuroinflammation, risk factors of neuroinflammation and pro-inflammatory cytokines in AD help us to understand AD pathogenesis and select therapeutic targets more efficiently.

Alzheimer’s Disease (AD); Pro-Inflammatory Cytokine; Neuroinflammation

1. Litke R, Garcharna LC, Jiwani SNeugroschl J. Modifiable Risk Factors in Alzheimer Disease and Related Dementias: A Review. Clinical therapeutics. 2021.
2. Scheltens P, Blennow K, Breteler M, De Strooper B, Frisoni GSalloway S. Van der Flier WM: Alzheimer’s disease. Lancet. 2016;388(10043):505-17.
3. Mayeux RStern Y. Epidemiology of Alzheimer disease. Cold Spring Harbor perspectives in medicine. 2012;2(8):a006239.
4. Grant WB, Campbell A, Itzhaki RFSavory J. The significance of environmental factors in the etiology of Alzheimer's disease. Journal of Alzheimer's Disease. 2002;4:179-89.
5. Khanahmadi M, Farhud DDMalmir M. Genetic of Alzheimer’s disease: A narrative review article. Iranian journal of public health. 2015;44(7):892.
6. Azizi GMirshafiey A. The potential role of proinflammatory and antiinflammatory cytokines in Alzheimer disease pathogenesis. Immunopharmacology and immunotoxicology. 2012;34(6):881-95.
7. Lanoiselée H-M, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLOS Medicine. 2017;14(3):e1002270.
8. Fuster-Matanzo A, Llorens-Martín M, Hernández FAvila J. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediators of inflammation. 2013;2013.
9. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204-18.
10. Fakhoury M. Microglia and astrocytes in Alzheimer's disease: Implications for therapy. Current neuropharmacology. 2018;16(5):508-18.
11. Leng FEdison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nature Reviews Neurology. 2020:1-16.
12. Zotova E, Nicoll JA, Kalaria R, Holmes CBoche D. Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimers Res Ther. 2010;2(1):1-9.
13. Lyman M, Lloyd DG, Ji X, Vizcaychipi MPMa D. Neuroinflammation: the role and consequences. Neuroscience research. 2014;79:1-12.
14. Augusto-Oliveira M, Arrifano GP, Lopes-Araújo A, Santos-Sacramento L, Takeda PY, Anthony DC, et al. What do microglia really do in healthy adult brain? Cells. 2019;8(10):1293.
15. Bourgognon J-MCavanagh J. The role of cytokines in modulating learning and memory and brain plasticity. Brain and Neuroscience Advances. 2020;4:2398212820979802.
16. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AMLamb BT. Inflammation as a central mechanism in Alzheimer's disease. Alzheimer's & Dementia: Translational Research & Clinical Interventions. 2018;4:575-90.
17. Sun Y, Ma C, Sun H, Wang H, Peng W, Zhou Z, et al. Metabolism: a novel shared link between diabetes mellitus and Alzheimer’s disease. Journal of diabetes research. 2020;2020.
18. de Araújo Boleti AP, de Oliveira Flores TM, Moreno SE, Dos Anjos L, Mortari MRMigliolo L. Neuroinflammation: An overview of neurodegenerative and metabolic diseases and of biotechnological studies. Neurochemistry international. 2020;136:104714.
19. Gauthier S, Aisen P, Cummings J, Detke M, Longo F, Raman R, et al. Non-amyloid approaches to disease modification for Alzheimer’s disease: an EU/US CTAD Task Force Report. The journal of prevention of Alzheimer's disease. 2020;7:152-57.
20. Gouras GK, Tampellini D, Takahashi RHCapetillo-Zarate E. Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease. Acta neuropathologica. 2010;119(5):523-41.
21. Thinakaran GKoo EH. Amyloid precursor protein trafficking, processing, and function. Journal of Biological Chemistry. 2008;283(44):29615-19.
22. Nalivaeva NNTurner AJ. The amyloid precursor protein: A biochemical enigma in brain development, function and disease. FEBS Letters. 2013;587(13):2046-54.
23. Volloch VRits S. Results of beta secretase-inhibitor clinical trials support amyloid precursor protein-independent generation of beta amyloid in sporadic Alzheimer’s disease. Medical Sciences. 2018;6(2):45.
24. Selkoe DJWolfe MS. Presenilin: running with scissors in the membrane. Cell. 2007;131(2):215-21.
25. Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, et al. Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Frontiers in cellular neuroscience. 2017;11:216.
26. Wang W, Zhao F, Ma X, Perry GZhu X. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. Molecular Neurodegeneration. 2020;15(1):1-22.
27. Kempuraj D, Mentor S, Thangavel R, Ahmed ME, Selvakumar GP, Raikwar SP, et al. Mast cells in stress, pain, blood-brain barrier, neuroinflammation and Alzheimer’s disease. Frontiers in cellular neuroscience. 2019:54.
28. Arranz AMDe Strooper B. The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications. The Lancet Neurology. 2019;18(4):406-14.
29. Chen G-f, Xu T-h, Yan Y, Zhou Y-r, Jiang Y, Melcher K, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacologica Sinica. 2017;38(9):1205-35.
30. Gao Y, Tan L, Yu JTTan L. Tau in Alzheimer's Disease: Mechanisms and Therapeutic Strategies. Curr Alzheimer Res. 2018;15(3):283-300.
31. Lee G, Newman ST, Gard DL, Band HPanchamoorthy G. Tau interacts with src-family non-receptor tyrosine kinases. Journal of cell science. 1998;111(21):3167-77.
32. Kitagishi Y, Nakanishi A, Ogura YMatsuda S. Dietary regulation of PI3K/AKT/GSK-3β pathway in Alzheimer’s disease. Alzheimer's research & therapy. 2014;6(3):1-7.
33. Li Y, Liu L, Barger SWGriffin WST. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. Journal of Neuroscience. 2003;23(5):1605-11.
34. Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, Olschowka JA, et al. Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. Journal of Neuroscience. 2013;33(11):5053-64.
35. Farfel JM, Yu L, De Jager PL, Schneider JABennett DA. Association of APOE with tau-tangle pathology with and without β-amyloid. Neurobiology of aging. 2016;37:19-25.
36. Bedse G, Di Domenico F, Serviddio GCassano T. Aberrant insulin signaling in Alzheimer's disease: current knowledge. Frontiers in neuroscience. 2015;9:204.
37. Gauthier S, Feldman HH, Schneider LS, Wilcock GK, Frisoni GB, Hardlund JH, et al. Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial. Lancet. 2016;388(10062):2873-84.
38. Congdon EESigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2018;14(7):399-415.
39. Griffin W, Stanley L, Ling C, White L, MacLeod V, Perrot L, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proceedings of the National Academy of Sciences. 1989;86(19):7611-15.
40. Grande G, Marengoni A, Vetrano DL, Roso‐Llorach A, Rizzuto D, Zucchelli A, et al. Multimorbidity burden and dementia risk in older adults: The role of inflammation and genetics. Alzheimer's & Dementia.
41. Borish LCSteinke JW. 2. Cytokines and chemokines. J Allergy Clin Immunol. 2003;111(2 Suppl):S460-75.
42. Sahibzada HA, Khurshid Z, Khan RS, Naseem M, Siddique KM, Mali M, et al. Salivary IL-8, IL-6 and TNF-α as potential diagnostic biomarkers for oral cancer. Diagnostics. 2017;7(2):21.
43. Kim YK, Na KS, Myint AMLeonard BE. The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:277-84.
44. Megur A, Baltriukienė D, Bukelskienė VBurokas A. The Microbiota–Gut–Brain Axis and Alzheimer’s Disease: Neuroinflammation Is to Blame? Nutrients. 2021;13(1):37.
45. Hoffman WH, Casanova MF, Cudrici CD, Zakranskaia E, Venugopalan R, Nag S, et al. Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis. Experimental and molecular pathology. 2007;83(1):65-72.
46. Liu B, Wang K, Gao HM, Mandavilli B, Wang JYHong JS. Molecular consequences of activated microglia in the brain: overactivation induces apoptosis. Journal of neurochemistry. 2001;77(1):182-89.
47. De Simone R, Ajmone-Cat MAMinghetti L. Atypical antiinflammatory activation of microglia induced by apoptotic neurons. Molecular neurobiology. 2004;29(2):197-212.
48. Smith JA, Das A, Ray SKBanik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain research bulletin. 2012;87(1):10-20.
49. Brown GCNeher JJ. Microglial phagocytosis of live neurons. Nature Reviews Neuroscience. 2014;15(4):209-16.
50. Dong YYong VW. When encephalitogenic T cells collaborate with microglia in multiple sclerosis. Nature Reviews Neurology. 2019;15(12):704-17.
51. Morianos I, Trochoutsou AI, Papadopoulou G, Semitekolou M, Banos A, Konstantopoulos D, et al. Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways. Proceedings of the National Academy of Sciences. 2020;117(22):12269-80.
52. Tesmer LA, Lundy SK, Sarkar SFox DA. Th17 cells in human disease. Immunological reviews. 2008;223:87-113.
53. Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature neuroscience. 2006;9(2):268-75.
54. Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. Journal of Experimental Medicine. 2010;207(5):1067-80.
55. Lei C, Wu B, Cao T, Liu MHao Z. Brain recovery mediated by toll-like receptor 4 in rats after intracerebral hemorrhage. Brain Research. 2016;1632:1-8.
56. Danilov AI, Covacu R, Moe MC, Langmoen IA, Johansson CB, Olsson T, et al. Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis. European Journal of Neuroscience. 2006;23(2):394-400.
57. Ishii H, Jin X, Ueno M, Tanabe S, Kubo T, Serada S, et al. Adoptive transfer of Th1-conditioned lymphocytes promotes axonal remodeling and functional recovery after spinal cord injury. Cell Death & Disease. 2012;3(8):e363-e63.
58. Hauben E, Butovsky O, Nevo U, Yoles E, Moalem G, Agranov E, et al. Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. Journal of Neuroscience. 2000;20(17):6421-30.
59. Yong HYF, Rawji KS, Ghorbani S, Xue MYong VW. The benefits of neuroinflammation for the repair of the injured central nervous system. Cellular & molecular immunology. 2019;16(6):540-46.
60. Plascencia-Villa GPerry G. Preventive and Therapeutic Strategies in Alzheimer's Disease: Focus on Oxidative Stress, Redox Metals, and Ferroptosis. Antioxidants and Redox Signaling. 2021;34(8):591-610.
61. Lashley T, Schott JM, Weston P, Murray CE, Wellington H, Keshavan A, et al. Molecular biomarkers of Alzheimer's disease: progress and prospects. Dis Model Mech. 2018;11(5).
62. Cai Y, Liu J, Wang B, Sun MYang H. Microglia in the neuroinflammatory pathogenesis of Alzheimer’s disease and related therapeutic targets. Frontiers in immunology. 2022:1868.
63. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz MAmit I. Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration. Cell. 2018;173(5):1073-81.
64. Ulland TKColonna M. TREM2—a key player in microglial biology and Alzheimer disease. Nature reviews neurology. 2018;14(11):667-75.
65. Yao KZu H-b. Microglial polarization: novel therapeutic mechanism against Alzheimer’s disease. Inflammopharmacology. 2020;28(1):95-110.
66. Cui W, Sun C, Ma Y, Wang S, Wang XZhang Y. Inhibition of TLR4 induces M2 microglial polarization and provides neuroprotection via the NLRP3 inflammasome in Alzheimer’s disease. Frontiers in neuroscience. 2020;14:444.
67. Rondinone CM. Adipocyte-derived hormones, cytokines, and mediators. Endocrine. 2006;29(1):81-90.
68. Wang W-Y, Tan M-S, Yu J-TTan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Annals of translational medicine. 2015;3(10):136-36.
69. Sastre M, Klockgether THeneka MT. Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. International Journal of Developmental Neuroscience. 2006;24(2-3):167-76.
70. Ojala J, Alafuzoff I, Herukka S-K, van Groen T, Tanila HPirttilä T. Expression of interleukin-18 is increased in the brains of Alzheimer's disease patients. Neurobiology of aging. 2009;30(2):198-209.
71. Abbas N, Bednar I, Mix E, Marie S, Paterson D, Ljungberg A, et al. Up-regulation of the inflammatory cytokines IFN-γ and IL-12 and down-regulation of IL-4 in cerebral cortex regions of APPSWE transgenic mice. Journal of neuroimmunology. 2002;126(1-2):50-57.
72. Mulder SD, Nielsen HM, Blankenstein MA, Eikelenboom PVeerhuis R. Apolipoproteins E and J interfere with amyloid‐beta uptake by primary human astrocytes and microglia in vitro. Glia. 2014;62(4):493-503.
73. Maezawa I, Zimin PI, Wulff HJin L-W. Amyloid-β protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. Journal of Biological Chemistry. 2011;286(5):3693-706.
74. Trojan E, Tylek K, Schröder N, Kahl I, Brandenburg L-O, Mastromarino M, et al. The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1–42)-Induced Neuroinflammation in Mouse Models of Alzheimer’s Disease. Molecular Neurobiology. 2021;58(12):6203-21.
75. Nakanishi A, Kaneko N, Takeda H, Sawasaki T, Morikawa S, Zhou W, et al. Amyloid β directly interacts with NLRP3 to initiate inflammasome activation: identification of an intrinsic NLRP3 ligand in a cell-free system. Inflamm Regen. 2018;38:27.
76. Bonaiuto C, McDonald PP, Rossi FCassatella MA. Activation of nuclear factor-kappa B by beta-amyloid peptides and interferon-gamma in murine microglia. J Neuroimmunol. 1997;77(1):51-6.
77. Ma L-Y, Liu S-F, Du J-H, Niu Y, Hou P-F, Shu Q, et al. Chronic ghrelin administration suppresses IKK/NF-κB/BACE1 mediated Aβ production in primary neurons and improves cognitive function via upregulation of PP1 in STZ-diabetic rats. Neurobiology of Learning and Memory. 2020;169:107155.
78. Qiao A, Li J, Hu Y, Wang JZhao Z. Reduction BACE1 expression via suppressing NF-κB mediated signaling by Tamibarotene in a mouse model of Alzheimer’s disease. IBRO Neuroscience Reports. 2021;10:153-60.
79. Swanson KV, Deng MTing JP-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology. 2019;19(8):477-89.
80. Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SAMiri SR. The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases. Genes & diseases. 2021;8(3):287-97.
81. Thawkar BSKaur G. Inhibitors of NF-κB and P2X7/NLRP3/Caspase 1 pathway in microglia: Novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease. Journal of neuroimmunology. 2019;326:62-74.
82. Hong Y, Liu Y, Yu D, Wang MHou Y. The neuroprotection of progesterone against Aβ-induced NLRP3-Caspase-1 inflammasome activation via enhancing autophagy in astrocytes. International Immunopharmacology. 2019;74:105669.
83. Blasko I, Stampfer‐Kountchev M, Robatscher P, Veerhuis R, Eikelenboom PGrubeck‐Loebenstein B. How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes. Aging cell. 2004;3(4):169-76.
84. De Vellis J. Neuroglia in the aging brain: Springer Science & Business Media; 2001.
85. Sidoryk-Wegrzynowicz M, Wegrzynowicz M, Lee E, Bowman ABAschner M. Role of astrocytes in brain function and disease. Toxicol Pathol. 2011;39(1):115-23.
86. Phillips EC, Croft CL, Kurbatskaya K, O’Neill MJ, Hutton ML, Hanger DP, et al. Astrocytes and neuroinflammation in Alzheimer's disease. Portland Press Ltd.; 2014.
87. Westacott LJ, Haan N, Evison C, Marei O, Hall J, Hughes TR, et al. Dissociable effects of complement C3 and C3aR on survival and morphology of adult born hippocampal neurons, pattern separation, and cognitive flexibility in male mice. Brain, Behavior, and Immunity. 2021;98:136-50.
88. Xu X, Zhang A, Zhu Y, He W, Di W, Fang Y, et al. MFG‐E8 reverses microglial‐induced neurotoxic astrocyte (A1) via NF‐κB and PI3K‐Akt pathways. Journal of Cellular physiology. 2019;234(1):904-14.
89. Tarczyluk MA, Nagel DA, Parri HR, Tse EH, Brown JE, Coleman MD, et al. Amyloid β 1-42 induces hypometabolism in human stem cell-derived neuron and astrocyte networks. Journal of Cerebral Blood Flow & Metabolism. 2015;35(8):1348-57.
90. Simpson IA, Chundu KR, Davies‐Hill T, Honer WGDavies P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer's disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 1994;35(5):546-51.
91. Simpson IA, Carruthers AVannucci SJ. Supply and demand in cerebral energy metabolism: the role of nutrient transporters. Journal of Cerebral Blood Flow & Metabolism. 2007;27(11):1766-91.
92. Berkenbosch F, Van Oers J, Del Rey A, Tilders FBesedovsky H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science. 1987;238(4826):524-26.
93. March CJ, Mosley B, Larsen A, Cerretti DP, Braedt G, Price V, et al. Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs. Nature. 1985;315(6021):641-47.
94. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, et al. A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes. Nature. 1992;356(6372):768-74.
95. Subramaniam S, Stansberg CCunningham C. The interleukin 1 receptor family. Developmental & Comparative Immunology. 2004;28(5):415-28.
96. Korherr C, Hofmeister R, Wesche HFalk W. A critical role for interleukin‐1 receptor accessory protein in interleukin‐1 signaling. European journal of immunology. 1997;27(1):262-67.
97. O'Léime CS, Cryan JFNolan YM. Nuclear deterrents: intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis. Brain, Behavior, and Immunity. 2017;66:394-412.
98. Molgora M, Supino D, Mantovani AGarlanda C. Tuning inflammation and immunity by the negative regulators IL‐1R2 and IL‐1R8. Immunological Reviews. 2018;281(1):233-47.
99. Allan SM, Tyrrell PJRothwell NJ. Interleukin-1 and neuronal injury. Nature Reviews Immunology. 2005;5(8):629-40.
100. Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990;343(6256):336-40.
101. Malyak M, Smith MF, Abel AA, Hance KRArend WP. The differential production of three forms of IL-1 receptor antagonist by human neutrophils and monocytes. The Journal of Immunology. 1998;161(4):2004-10.
102. Du Y, Dodel R, Eastwood B, Bales K, Gao F, Lohmüller F, et al. Association of an interleukin 1α polymorphism with Alzheimer’s disease. Neurology. 2000;55(4):480-84.
103. Grimaldi LM, Casadei VM, Ferri C, Veglia F, Licastro F, Annoni G, et al. Association of early‐onset Alzheimer's disease with an interleukin‐1α gene polymorphism. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2000;47(3):361-65.
104. Déniz‐Naranjo M, Muñoz‐Fernandez C, Alemany‐Rodríguez M, Pérez‐Vieitez M, Aladro‐Benito Y, Irurita‐Latasa J, et al. Cytokine IL‐1 beta but not IL‐1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Canary Islands, Spain. European journal of neurology. 2008;15(10):1080-84.
105. Babić Leko M, Nikolac Perković M, Klepac N, Štrac DŠ, Borovečki F, Pivac N, et al. IL-1β, IL-6, IL-10, and TNF α Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology. Journal of Alzheimer's Disease. 2020(Preprint):1-19.
106. Mason JL, Suzuki K, Chaplin DDMatsushima GK. Interleukin-1β promotes repair of the CNS. Journal of Neuroscience. 2001;21(18):7046-52.
107. Landgraf R, Neumann I, Holsboer FPittman QJ. Interleukin‐1β stimulates both central and peripheral release of vasopressin and oxytocin in the rat. European Journal of Neuroscience. 1995;7(4):592-98.
108. Sapolsky R, Rivier C, Yamamoto G, Plotsky PVale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science. 1987;238(4826):522-24.
109. Uehara A, Gottschall PE, Dahl RRArimura A. Interleukin-1 stimulates ACTH release by an indirect action which requires endogenous corticotropin releasing factor. Endocrinology. 1987;121(4):1580-82.
110. Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen JS, et al. Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proceedings of the National Academy of Sciences. 1989;86(19):7606-10.
111. Basu A, Krady JKLevison SW. Interleukin‐1: a master regulator of neuroinflammation. Journal of neuroscience research. 2004;78(2):151-56.
112. Kopitar-Jerala N. Innate Immune Response in Brain, NF-Kappa B Signaling and Cystatins. Frontiers in Molecular Neuroscience. 2015;8(73).
113. Shang D, Hong Y, Xie W, Tu ZXu J. Interleukin-1β Drives Cellular Senescence of Rat Astrocytes Induced by Oligomerized Amyloid β Peptide and Oxidative Stress. Frontiers in Neurology. 2020;11.
114. John GR, Lee SC, Song X, Rivieccio MBrosnan CF. IL‐1‐regulated responses in astrocytes: Relevance to injury and recovery. Glia. 2005;49(2):161-76.
115. Wyble CW, Hynes KL, Kuchibhotla J, Marcus BC, Hallahan DGewertz BL. TNF-alpha and IL-1 upregulate membrane-bound and soluble E-selectin through a common pathway. J Surg Res. 1997;73(2):107-12.
116. Calkins CM, Bensard DD, Shames BD, Pulido EJ, Abraham E, Fernandez N, et al. IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia. J Endotoxin Res. 2002;8(1):59-67.
117. Allan SMRothwell NJ. Cytokines and acute neurodegeneration. Nature Reviews Neuroscience. 2001;2(10):734-44.
118. Dubois C, Prevarskaya NAbeele F. The calcium-signaling toolkit: Updates needed. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2015;1863.
119. Yang S, Liu Z-W, Wen L, Qiao H-F, Zhou W-XZhang Y-X. Interleukin-1β enhances NMDA receptor-mediated current but inhibits excitatory synaptic transmission. Brain research. 2005;1034(1-2):172-79.
120. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens M, Bartfai T, et al. Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. Journal of neuroscience. 2003;23(25):8692-700.
121. Marambaud P, Dreses-Werringloer UVingtdeux V. Calcium signaling in neurodegeneration. Mol Neurodegener. 2009;4:20.
122. Pivovarova NBAndrews SB. Calcium-dependent mitochondrial function and dysfunction in neurons. The FEBS journal. 2010;277(18):3622-36.
123. Guo Y, Hao DHu H. High doses of dexamethasone induce endoplasmic reticulum stress-mediated apoptosis by promoting calcium ion influx-dependent CHOP expression in osteoblasts. Molecular Biology Reports. 2021;48(12):7841-51.
124. Urbańska-Ryś H, Wiersbowska A, Stepień HRobak T. Relationship between circulating interleukin-10 (IL-10) with interleukin-6 (IL-6) type cytokines (IL-6, interleukin-11 (IL-11), oncostatin M (OSM)) and soluble interleukin-6 (IL-6) receptor (sIL-6R) in patients with multiple myeloma. European cytokine network. 2000;11(3):443-51.
125. Rose-John S. Interleukin-6 family cytokines. Cold Spring Harbor perspectives in biology. 2018;10(2):a028415.
126. Murakami M, Kamimura DHirano T. Mini ReviewNew IL-6 (gp130) Family Cytokine Members, CLC/NNT1/BSF3 and IL-27. Growth Factors. 2004;22(2):75-77.
127. Boulanger MJ, Chow D-c, Brevnova EEGarcia KC. Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex. Science. 2003;300(5628):2101-04.
128. Simpson RJ, Hammacher A, Smith DK, Matthews JMWard LD. Interleukin‐6: Structure‐function relationships. Protein Science. 1997;6(5):929-55.
129. Wolf J, Rose-John SGarbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70(1):11-20.
130. Jones SA, Scheller JRose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. The Journal of clinical investigation. 2011;121(9):3375-83.
131. Garbers C, Aparicio-Siegmund SRose-John S. The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition. Current opinion in immunology. 2015;34:75-82.
132. Ishibashi T, Kimura H, Uchida T, Kariyone S, Friese PBurstein SA. Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proceedings of the National Academy of Sciences. 1989;86(15):5953-57.
133. Chalaris A, Garbers C, Rabe B, Rose-John SScheller J. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. European journal of cell biology. 2011;90(6-7):484-94.
134. Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. International journal of biological sciences. 2012;8(9):1237.
135. Haegeman G, Content J, Volckaert G, Derynck R, Tavernier JFiers W. Structural analysis of the sequence coding for an inducible 26‐kDa protein in human fibroblasts. European journal of biochemistry. 1986;159(3):625-32.
136. Kushner I, Jiang S-L, Zhang D, Lozanski GSamols D. Do post-transcriptional mechanisms participate in induction of C-reactive protein and serum amyloid A by IL-6 and IL-1? Annals of the New York Academy of Sciences-Paper Edition. 1995;762:102-07.
137. Ringheim GE, Szczepanik AM, Petko W, Burgher KL, Zu Zhu SChao CC. Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor/interleukin-6 complex. Molecular Brain Research. 1998;55(1):35-44.
138. Peter C, BEHRMANN I, Gerhard M, LLER-NEWEN FSGRAEVE L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway1. Biochem. J. 1998;334:297-314.
139. Ait‐Ghezala G, Volmar CH, Frieling J, Paris D, Tweed M, Bakshi P, et al. CD40 promotion of amyloid beta production occurs via the NF‐κB pathway. European Journal of Neuroscience. 2007;25(6):1685-95.
140. Forloni G, Mangiarotti F, Angeretti N, Lucca EDe Simoni MG. β-amyloid fragment potentiates IL-6 and TNF-α secretion by LPS in astrocytes but not in microglia. Cytokine. 1997;9(10):759-62.
141. Rothaug M, Becker-Pauly CRose-John S. The role of interleukin-6 signaling in nervous tissue. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2016;1863(6, Part A):1218-27.
142. Ben Haim L, Ceyzériat K, Carrillo-de Sauvage MA, Aubry F, Auregan G, Guillermier M, et al. The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's diseases. J Neurosci. 2015;35(6):2817-29.
143. Reichenbach N, Delekate A, Plescher M, Schmitt F, Krauss S, Blank N, et al. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer's disease model. EMBO molecular medicine. 2019;11(2):e9665.
144. Gadient ROtten U. Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development. Brain research. 1994;637(1-2):10-14.
145. Braida D, Sacerdote P, Panerai AE, Bianchi M, Aloisi AM, Iosuè S, et al. Cognitive function in young and adult IL (interleukin)-6 deficient mice. Behavioural brain research. 2004;153(2):423-29.
146. Toulmond S, Vige X, Fage DBenavides J. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neuroscience letters. 1992;144(1-2):49-52.
147. Lanzrein A-S, Johnston CM, Perry VH, Jobst KA, King EMSmith AD. Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. Alzheimer disease and associated disorders. 1998;12(3):215-27.
148. Huberman M, Sredni B, Stern L, Kott EShalit F. IL-2 and IL-6 secretion in dementia: correlation with type and severity of disease. J Neurol Sci. 1995;130(2):161-4.
149. Cojocaru IM, Cojocaru M, Miu GSapira V. Study of interleukin-6 production in Alzheimer's disease. Rom J Intern Med. 2011;49(1):55-8.
150. Kindy MS, Yu J, Guo JTZhu H. Apolipoprotein Serum Amyloid A in Alzheimer's Disease. J Alzheimers Dis. 1999;1(3):155-67.
151. Jang S, Jang WY, Choi M, Lee J, Kwon W, Yi J, et al. Serum amyloid A1 is involved in amyloid plaque aggregation and memory decline in amyloid beta abundant condition. Transgenic Res. 2019;28(5-6):499-508.
152. Quintanilla RA, Orellana DI, González-Billault CMaccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Experimental Cell Research. 2004;295(1):245-57.
153. Morales I, Farías GMaccioni RB. Neuroimmunomodulation in the pathogenesis of Alzheimer’s disease. Neuroimmunomodulation. 2010;17(3):202-04.
154. Rothaug M, Becker-Pauly CRose-John S. The role of interleukin-6 signaling in nervous tissue. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2016;1863(6):1218-27.
155. Ivanov II, Zhou LLittman DR, editors. Transcriptional regulation of Th17 cell differentiation. Seminars in immunology; 2007: Elsevier.
156. Morishima N, Mizoguchi I, Takeda K, Mizuguchi JYoshimoto T. TGF-β is necessary for induction of IL-23R and Th17 differentiation by IL-6 and IL-23. Biochemical and biophysical research communications. 2009;386(1):105-10.
157. Chakrabarty P, Jansen‐West K, Beccard A, Ceballos‐Diaz C, Levites Y, Verbeeck C, et al. Massive gliosis induced by interleukin‐6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. The FASEB Journal. 2010;24(2):548-59.
158. Carswell EA, Old LJ, Kassel R, Green S, Fiore NWilliamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the National Academy of Sciences. 1975;72(9):3666-70.
159. Laws SM, Perneczky R, Wagenpfeil S, Müller U, Förstl H, Martins RN, et al. TNF polymorphisms in Alzheimer disease and functional implications on CSF beta‐amyloid levels. Human mutation. 2005;26(1):29-35.
160. Luettig B, Decker TLohmann-Matthes M. Evidence for the existence of two forms of membrane tumor necrosis factor: an integral protein and a molecule attached to its receptor. The Journal of Immunology. 1989;143(12):4034-38.
161. Kriegler M, Perez C, DeFay K, Albert ILu S. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988;53(1):45-53.
162. McAlpine FE, Lee J-K, Harms AS, Ruhn KA, Blurton-Jones M, Hong J, et al. Inhibition of soluble TNF signaling in a mouse model of Alzheimer's disease prevents pre-plaque amyloid-associated neuropathology. Neurobiology of disease. 2009;34(1):163-77.
163. Alexopoulou L, Kranidioti K, Xanthoulea S, Denis M, Kotanidou A, Douni E, et al. Transmembrane TNF protects mutant mice against intracellular bacterial infections, chronic inflammation and autoimmunity. European journal of immunology. 2006;36(10):2768-80.
164. Ware CF. Tumor Necrosis Factors. In: Bertino JR, editor. Encyclopedia of Cancer (Second Edition). New York: Academic Press; 2002. p. 475-89.
165. Kinouchi K, Brown G, Pasternak GDonner DB. Identification and characterization of receptors for tumor necrosis factor-alpha in the brain. Biochem Biophys Res Commun. 1991;181(3):1532-8.
166. Cheng B, Christakos SMattson MP. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron. 1994;12(1):139-53.
167. Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nature Reviews Cancer. 2002;2(6):420-30.
168. Rothe J, Lesslauer W, Lötscher H, Lang Y, Koebel P, Köntgen F, et al. Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature. 1993;364(6440):798-802.
169. van Horssen R, Ten Hagen TLEggermont AM. TNF‐α in cancer treatment: molecular insights, antitumor effects, and clinical utility. The oncologist. 2006;11(4):397-408.
170. Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, et al. Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. The American journal of pathology. 2007;170(2):680-92.
171. Blasko I, Marx F, Steiner E, Hartmann TGrubeck‐Loebenstein B. TNFα plus IFNγ induce the production of Alzheimer β‐amyloid peptides and decrease the secretion of APPs. The FASEB journal. 1999;13(1):63-68.
172. Osborn L, Kunkel SNabel GJ. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proceedings of the National Academy of Sciences. 1989;86(7):2336-40.
173. Chang R, Yee K-LSumbria RK. Tumor necrosis factor α Inhibition for Alzheimer's Disease. Journal of central nervous system disease. 2017;9:1179573517709278-78.
174. Hövelmeyer N, Hao Z, Kranidioti K, Kassiotis G, Buch T, Frommer F, et al. Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis. The Journal of Immunology. 2005;175(9):5875-84.
175. Shen J, T-To SS, Schrieber LKing N. Early E-selectin, VCAM-1, ICAM-1, and late major histocompatibility complex antigen induction on human endothelial cells by flavivirus and comodulation of adhesion molecule expression by immune cytokines. Journal of Virology. 1997;71(12):9323-32.
176. Fonseca SG, Romão PR, Figueiredo F, Morais RH, Lima HC, Ferreira SH, et al. TNF-alpha mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis. Eur J Immunol. 2003;33(8):2297-306.
177. Edwards MRobinson SR. TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer’s disease. Journal of Neural Transmission. 2006;113(11):1709-15.
178. Monje ML, Toda HPalmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302(5651):1760-65.
179. Chen ZPalmer TD. Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis. Brain, behavior, and immunity. 2013;30:45-53.
180. Busquets S, Aranda X, Ribas-Carbo M, Azcon-Bieto J, López-Soriano FJArgilés JM. Tumour necrosis factor-alpha uncouples respiration in isolated rat mitochondria. Cytokine. 2003;22(1-2):1-4.
181. Oeckinghaus AGhosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harbor perspectives in biology. 2009;1(4):a000034.
182. Sun S-C, Chang J-HJin J. Regulation of nuclear factor-κB in autoimmunity. Trends in immunology. 2013;34(6):282-89.
183. Beinke SLey SC. Functions of NF-κB1 and NF-κB2 in immune cell biology. Biochemical Journal. 2004;382(2):393-409.
184. Almowallad S, Alqahtani LSMobashir M. NF-kB in Signaling Patterns and Its Temporal Dynamics Encode/Decode Human Diseases. Life. 2022;12(12):2012.
185. Liu T, Zhang L, Joo DSun S-C. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy. 2017;2(1):17023.
186. Vallabhapurapu SKarin M. Regulation and function of NF-κB transcription factors in the immune system. Annual review of immunology. 2009;27:693-733.
187. Sun S-C. Non-canonical NF-κB signaling pathway. Cell research. 2011;21(1):71-85.
188. Sun S-CLey SC. New insights into NF-κB regulation and function. Trends in immunology. 2008;29(10):469-78.
189. Karin MDelhase M, editors. The IκB kinase (IKK) and NF-κB: key elements of proinflammatory signalling. Seminars in immunology; 2000: Elsevier.
190. Israël A. The IKK complex, a central regulator of NF-κB activation. Cold Spring Harbor perspectives in biology. 2010;2(3):a000158.
191. Zhang HSun S-C. NF-κB in inflammation and renal diseases. Cell & bioscience. 2015;5(1):1-12.
192. Hayden MSGhosh S. Shared principles in NF-κB signaling. Cell. 2008;132(3):344-62.
193. Lampl S, Janas MK, Donakonda S, Brugger M, Lohr K, Schneider A, et al. Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. Journal of hepatology. 2020;73(6):1347-59.
194. Choudhary S, Kalita M, Fang L, Patel KV, Tian B, Zhao Y, et al. Inducible tumor necrosis factor (TNF) receptor-associated factor-1 expression couples the canonical to the non-canonical NF-κB pathway in TNF stimulation. Journal of Biological Chemistry. 2013;288(20):14612-23.
195. Sun S-CLiu Z-G. A special issue on NF-κB signaling and function. Cell research. 2011;21(1):1-2.
196. Sun SC. The noncanonical NF‐κB pathway. Immunological reviews. 2012;246(1):125-40.
197. Yu H, Lin L, Zhang Z, Zhang HHu H. Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study. Signal transduction and targeted therapy. 2020;5(1):1-23.
198. Morgan D, Garg M, Tergaonkar V, Tan SYSethi G. Pharmacological significance of the non-canonical NF-κB pathway in tumorigenesis. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2020;1874(2):188449.
199. House CD, Grajales V, Ozaki M, Jordan E, Wubneh H, Kimble DC, et al. IΚΚε cooperates with either MEK or non-canonical NF-kB driving growth of triple-negative breast cancer cells in different contexts. BMc cancer. 2018;18(1):1-13.
200. Pippione AC, Sainas S, Federico A, Lupino E, Piccinini M, Kubbutat M, et al. N-Acetyl-3-aminopyrazoles block the non-canonical NF-kB cascade by selectively inhibiting NIK. MedChemComm. 2018;9(6):963-68.
201. Bobardt M, Kuo J, Chatterji U, Chanda S, Little SJ, Wiedemann N, et al. The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate. PLoS One. 2019;14(2):e0211746.
202. AlQasrawi D, Naser ENaser SA. Nicotine increases macrophage survival through α7nAChR/NF-κB pathway in Mycobacterium avium paratuberculosis infection. Microorganisms. 2021;9(5):1086.
203. Jimi EKatagiri T. Critical roles of NF-κB signaling molecules in bone metabolism revealed by genetic mutations in osteopetrosis. International journal of molecular sciences. 2022;23(14):7995.
204. Xiang H, Zhu F, Xu ZXiong J. Role of inflammasomes in kidney diseases via both canonical and non-canonical pathways. Frontiers in cell and developmental biology. 2020;8:106.
205. Zhu J, Yamane HPaul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010;28:445-89.
206. Oh HGhosh S. NF-κB: roles and regulation in different CD4(+) T-cell subsets. Immunol Rev. 2013;252(1):41-51.
207. Aronica MA, Mora AL, Mitchell DB, Finn PW, Johnson JE, Sheller JR, et al. Preferential role for NF-κB/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo. The Journal of Immunology. 1999;163(9):5116-24.
208. Li Y, Wang H, Zhou X, Xie X, Chen X, Jie Z, et al. Cell intrinsic role of NF-κB-inducing kinase in regulating T cell-mediated immune and autoimmune responses. Scientific reports. 2016;6(1):1-11.
209. Murray SE, Polesso F, Rowe AM, Basak S, Koguchi Y, Toren KG, et al. NF-κB–inducing kinase plays an essential T cell–intrinsic role in graft-versus-host disease and lethal autoimmunity in mice. The Journal of clinical investigation. 2011;121(12).
210. Rowe AM, Murray SE, Raué H-P, Koguchi Y, Slifka MKParker DC. A Cell-Intrinsic Requirement for NF-κB–Inducing Kinase in CD4 and CD8 T Cell Memory. The Journal of Immunology. 2013;191(7):3663-72.
211. Yu J, Wang Y, Yan F, Zhang P, Li H, Zhao H, et al. Noncanonical NF-κB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer. The Journal of Immunology. 2014;193(5):2574-86.
212. Grilli M, Ribola M, Alberici A, Valerio A, Memo MSpano P. Amyloid precursor protein (APP) gene expression is controlled by a NFkB/Rel related protein. Alzheimer’s and Parkinson’s Diseases: Springer; 1995. p. 105-10.
213. Chen C-H, Zhou W, Liu S, Deng Y, Cai F, Tone M, et al. Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. International Journal of Neuropsychopharmacology. 2012;15(1):77-90.
214. Sadagurski M, Cady GMiller RA. Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner. Aging Cell. 2017;16(4):652-60.
215. Egaña-Gorroño L, López-Díez R, Yepuri G, Ramirez LS, Reverdatto S, Gugger PF, et al. Receptor for advanced glycation end products (RAGE) and mechanisms and therapeutic opportunities in diabetes and cardiovascular disease: insights from human subjects and animal models. Frontiers in cardiovascular medicine. 2020;7:37.
216. Kong Y, Liu C, Zhou Y, Qi J, Zhang C, Sun B, et al. Progress of RAGE molecular imaging in Alzheimer’s disease. Frontiers in Aging Neuroscience. 2020;12:227.
217. Park S-S, Park H-S, Kim C-J, Baek S-S, Park S-Y, Anderson C, et al. Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer’s disease of 3× Tg mice. Journal of Applied Physiology. 2022;132(4):1054-68.
218. Wang G, Wang X, Zheng X, Sun S, Zhao J, Long Y, et al. Acidic oligosaccharide sugar chain combined with hyperbaric oxygen delays D-galactose-induced brain senescence in mice via attenuating oxidative stress and neuroinflammation. Neuroscience Research. 2022.
219. Gonzalez-Reyes RERubiano MG. Astrocyte s RAGE: more than just a question of mood. Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents). 2018;18(1):39-48.
220. Morris M, Evans D, Bienias J, Tangney C, Wilson R, Qu W, et al. Tao WY, Yu LJ, Jiang S, Cao X, Chen J, Bao XY, Li F, Xu Y, Zhu XL (2020) Neuroprotective effects of ZL006 in Aβ1–42-treated neuronal cells. Neural Regen Res 15 (12): 2296-2305. doi: 10.4103/1673-5374.285006. J Neurosci.19:5360-69.
221. Logsdon AF, Meabon JS, Cline MM, Bullock KM, Raskind MA, Peskind ER, et al. Blast exposure elicits blood-brain barrier disruption and repair mediated by tight junction integrity and nitric oxide dependent processes. Scientific reports. 2018;8(1):1-13.
222. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, Hogg E, et al. RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain. Nature medicine. 2003;9(7):907-13.
223. Versele R, Sevin E, Gosselet F, Fenart LCandela P. TNF-α and IL-1β Modulate Blood-Brain Barrier Permeability and Decrease Amyloid-β Peptide Efflux in a Human Blood-Brain Barrier Model. International Journal of Molecular Sciences. 2022;23(18):10235.
224. Swanson KV, Deng MTing JPY. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology. 2019;19(8):477-89.
225. Guo H, Callaway JBTing JPY. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine. 2015;21(7):677-87.
226. Ketelut-Carneiro NFitzgerald KA. Inflammasomes. Curr Biol. 2020;30(12):R689-r94.
227. Li T, Lu L, Pember E, Li X, Zhang BZhu Z. New insights into neuroinflammation involved in pathogenic mechanism of Alzheimer’s disease and its potential for therapeutic intervention. Cells. 2022;11(12):1925.
228. Yang Y, Wang H, Kouadir M, Song HShi F. Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors. Cell Death & Disease. 2019;10(2):128.
229. Rahman T, Nagar A, Duffy EB, Okuda K, Silverman NHarton JA. NLRP3 sensing of diverse inflammatory stimuli requires distinct structural features. Frontiers in immunology. 2020;11:1828.
230. Zheng D, Liwinski TElinav E. Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discovery. 2020;6(1):36.
231. Akbal A, Dernst A, Lovotti M, Mangan MSJ, McManus RMLatz E. How location and cellular signaling combine to activate the NLRP3 inflammasome. Cellular & Molecular Immunology. 2022;19(11):1201-14.
232. Kelley N, Jeltema D, Duan YHe Y. The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci. 2019;20(13).
233. Oroz J, Barrera-Vilarmau S, Alfonso C, Rivas Gde Alba E. ASC Pyrin Domain Self-associates and Binds NLRP3 Protein Using Equivalent Binding Interfaces. J Biol Chem. 2016;291(37):19487-501.
234. Dekker C, Mattes H, Wright M, Boettcher A, Hinniger A, Hughes N, et al. Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition. J Mol Biol. 2021;433(24):167309.
235. He Y, Zeng MY, Yang D, Motro BNúñez G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 2016;530(7590):354-57.
236. Chen JChen ZJ. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature. 2018;564(7734):71-76.
237. Bergsbaken T, Fink SLCookson BT. Pyroptosis: host cell death and inflammation. Nature Reviews Microbiology. 2009;7(2):99-109.
238. Felderhoff-Mueser U, Schmidt OI, Oberholzer A, Bührer CStahel PF. IL-18: a key player in neuroinflammation and neurodegeneration? Trends in neurosciences. 2005;28(9):487-93.
239. Lamkanfi MDixit VM. Mechanisms and functions of inflammasomes. Cell. 2014;157(5):1013-22.
240. Gustin A, Kirchmeyer M, Koncina E, Felten P, Losciuto S, Heurtaux T, et al. NLRP3 inflammasome is expressed and functional in mouse brain microglia but not in astrocytes. PloS one. 2015;10(6):e0130624.
241. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature immunology. 2008;9(8):857-65.
242. Yap JKY, Pickard BS, Chan EWLGan SY. The role of neuronal NLRP1 inflammasome in Alzheimer’s disease: bringing neurons into the neuroinflammation game. Molecular neurobiology. 2019;56(11):7741-53.
243. Tejera D, Mercan D, Sanchez-Caro JM, Hanan M, Greenberg D, Soreq H, et al. Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome. Embo j. 2019;38(17):e101064.
244. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674-8.
245. Bouchon A, Dietrich JColonna M. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. The Journal of Immunology. 2000;164(10):4991-95.
246. Bouchon A, Hernández-Munain C, Cella MColonna M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. The Journal of experimental medicine. 2001;194(8):1111-22.
247. Hu N, Tan M-S, Yu J-T, Sun L, Tan L, Wang Y-L, et al. Increased expression of TREM2 in peripheral blood of Alzheimer's disease patients. Journal of Alzheimer's Disease. 2014;38(3):497-501.
248. Colonna M. TREMs in the immune system and beyond. Nature Reviews Immunology. 2003;3(6):445-53.
249. Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J, et al. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiology of aging. 2013;34(12):2699-714.
250. Bhattacharjee S, Zhao Y, Dua P, Rogaev EILukiw WJ. microRNA-34a-mediated down-regulation of the microglial-enriched triggering receptor and phagocytosis-sensor TREM2 in age-related macular degeneration. PloS one. 2016;11(3):e0150211.
251. Zheng H, Liu C-C, Atagi Y, Chen X-F, Jia L, Yang L, et al. Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation. Neurobiology of aging. 2016;42:132-41.
252. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, et al. Cutting edge: TREM-2 attenuates macrophage activation. The Journal of Immunology. 2006;177(6):3520-24.
253. Gratuze M, Leyns CEGHoltzman DM. New insights into the role of TREM2 in Alzheimer’s disease. Molecular Neurodegeneration. 2018;13(1):66.
254. Sun M, Zhu M, Chen K, Nie X, Deng Q, Hazlett LD, et al. TREM-2 promotes host resistance against Pseudomonas aeruginosa infection by suppressing corneal inflammation via a PI3K/Akt signaling pathway. Investigative ophthalmology & visual science. 2013;54(5):3451-62.
255. Sada K, Takano T, Yanagi SYamamura H. Structure and function of Syk protein-tyrosine kinase. The Journal of Biochemistry. 2001;130(2):177-86.
256. Mócsai A, Ruland JTybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nature Reviews Immunology. 2010;10(6):387-402.
257. Takahashi K, Rochford CDNeumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. The Journal of experimental medicine. 2005;201(4):647-57.
258. Lanier LL, Corliss BC, Wu J, Leong CPhillips JH. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature. 1998;391(6668):703-07.
259. Call ME, Wucherpfennig KWChou JJ. The structural basis for intramembrane assembly of an activating immunoreceptor complex. Nature immunology. 2010;11(11):1023-29.
260. Saber M, Kokiko-Cochran O, Puntambekar SS, Lathia JDLamb BT. Triggering receptor expressed on myeloid cells 2 deficiency alters acute macrophage distribution and improves recovery after traumatic brain injury. Journal of neurotrauma. 2017;34(2):423-35.
261. Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. Journal of Neuroscience. 2015;35(8):3384-96.
262. Takahashi K, Prinz M, Stagi M, Chechneva ONeumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS medicine. 2007;4(4):e124.
263. Atagi Y, Liu C-C, Painter MM, Chen X-F, Verbeeck C, Zheng H, et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). Journal of Biological Chemistry. 2015;290(43):26043-50.
264. Li R, Zhang J, Wang Q, Cheng MLin B. TPM1 mediates inflammation downstream of TREM2 via the PKA/CREB signaling pathway. Journal of Neuroinflammation. 2022;19(1):1-22.
265. Kobayashi M, Konishi H, Sayo A, Takai TKiyama H. TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain. Journal of Neuroscience. 2016;36(43):11138-50.
266. Gratuze M, Chen Y, Parhizkar S, Jain N, Strickland MR, Serrano JR, et al. Activated microglia mitigate Aβ-associated tau seeding and spreading. Journal of Experimental Medicine. 2021;218(8):e20210542.
267. Zhao Y, Wu X, Li X, Jiang L-L, Gui X, Liu Y, et al. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron. 2018;97(5):1023-31. e7.
268. Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NKSeaman WE. Pattern recognition by TREM-2: binding of anionic ligands. The Journal of Immunology. 2003;171(2):594-99.
269. Meilandt WJ, Ngu H, Gogineni A, Lalehzadeh G, Lee S-H, Srinivasan K, et al. Trem2 deletion reduces late-stage amyloid plaque accumulation, elevates the Aβ42: Aβ40 ratio, and exacerbates axonal dystrophy and dendritic spine loss in the PS2APP Alzheimer's mouse model. Journal of Neuroscience. 2020;40(9):1956-74.
270. Gratuze M, Leyns CE, Sauerbeck AD, St-Pierre M-K, Xiong M, Kim N, et al. Impact of TREM2 R47H variant on tau pathology–induced gliosis and neurodegeneration. The Journal of clinical investigation. 2020;130(9):4954-68.
271. Cosker K, Mallach A, Limaye J, Piers TM, Staddon J, Neame SJ, et al. Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome. Scientific Reports. 2021;11(1):1-15.
272. Chen S, Peng J, Sherchan P, Ma Y, Xiang S, Yan F, et al. TREM2 activation attenuates neuroinflammation and neuronal apoptosis via PI3K/Akt pathway after intracerebral hemorrhage in mice. Journal of neuroinflammation. 2020;17(1):1-16.
273. Decout A, Katz JD, Venkatraman SAblasser A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nature Reviews Immunology. 2021;21(9):548-69.
274. Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, et al. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. Proceedings of the National Academy of Sciences. 2019;116(24):11946-55.
275. Zhang X, Wu J, Du F, Xu H, Sun L, Chen Z, et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell reports. 2014;6(3):421-30.
276. Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL, Zillinger T, et al. Cyclic [G (2′, 5′) pA (3′, 5′) p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell. 2013;153(5):1094-107.
277. Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498(7454):332-37.
278. Ishikawa H, Ma ZBarber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461(7265):788-92.
279. Ishikawa HBarber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455(7213):674-78.
280. Liu D, Wu H, Wang C, Li Y, Tian H, Siraj S, et al. STING directly activates autophagy to tune the innate immune response. Cell Death & Differentiation. 2019;26(9):1735-49.
281. Prabakaran T, Bodda C, Krapp C, Zhang Bc, Christensen MH, Sun C, et al. Attenuation of c GAS‐STING signaling is mediated by a p62/SQSTM 1‐dependent autophagy pathway activated by TBK1. The EMBO journal. 2018;37(8):e97858.
282. Gui X, Yang H, Li T, Tan X, Shi P, Li M, et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature. 2019;567(7747):262-66.
283. Margolis SR, Wilson SCVance RE. Evolutionary origins of cGAS-STING signaling. Trends in immunology. 2017;38(10):733-43.
284. Nassour J, Radford R, Correia A, Fusté JM, Schoell B, Jauch A, et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature. 2019;565(7741):659-63.
285. Gulen MF, Koch U, Haag SM, Schuler F, Apetoh L, Villunger A, et al. Signalling strength determines proapoptotic functions of STING. Nature communications. 2017;8(1):1-10.
286. Glück S, Guey B, Gulen MF, Wolter K, Kang T-W, Schmacke NA, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nature cell biology. 2017;19(9):1061-70.
287. Zierhut C, Yamaguchi N, Paredes M, Luo J-D, Carroll TFunabiki H. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell. 2019;178(2):302-15. e23.
288. Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proceedings of the National Academy of Sciences. 2013;110(41):16544-49.
289. Liu SGuan W. STING signaling promotes apoptosis, necrosis, and cell death: an overview and update. Mediators of Inflammation. 2018;2018.
290. White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ, et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell. 2014;159(7):1549-62.
291. Morgan MJKim Y-S. Roles of RIPK3 in necroptosis, cell signaling, and disease. Experimental & molecular medicine. 2022:1-10.
292. Brault M, Olsen TM, Martinez J, Stetson DBOberst A. Intracellular nucleic acid sensing triggers necroptosis through synergistic type I IFN and TNF signaling. The Journal of Immunology. 2018;200(8):2748-56.
293. DeRoo E, Zhou TLiu B. The role of RIPK1 and RIPK3 in cardiovascular disease. International Journal of Molecular Sciences. 2020;21(21):8174.
294. Hui CW, Zhang YHerrup K. Non-Neuronal Cells Are Required to Mediate the Effects of Neuroinflammation: Results from a Neuron-Enriched Culture System. PLoS One. 2016;11(1):e0147134.
295. Chen K, Lai C, Su Y, Bao WD, Yang LN, Xu P-P, et al. cGAS-STING-mediated IFN-I Response in Host Defense and Neuroinflammatory Diseases. Current Neuropharmacology. 2022;20(2):362-71.
296. Tan P-H, Ji J, Hsing C-H, Tan RJi R-R. Emerging Roles of Type-I Interferons in Neuroinflammation, Neurological Diseases, and Long-Haul COVID. International Journal of Molecular Sciences. 2022;23(22):14394.
297. Wang W, Hu D, Wu C, Feng Y, Li A, Liu W, et al. STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection. PLoS pathogens. 2020;16(3):e1008335.
298. Jin M, Shiwaku H, Tanaka H, Obita T, Ohuchi S, Yoshioka Y, et al. Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation. Nature communications. 2021;12(1):1-22.
299. Zhao J, Xu C, Cao H, Zhang L, Wang XChen S. Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats. PeerJ. 2019;7:e8324.
300. Boyd RJ, Avramopoulos D, Jantzie LLMcCallion AS. Neuroinflammation represents a common theme amongst genetic and environmental risk factors for Alzheimer and Parkinson diseases. Journal of Neuroinflammation. 2022;19(1):223.
301. Fraser PE, Yang D-S, Yu G, Lévesque L, Nishimura M, Arawaka S, et al. Presenilin structure, function and role in Alzheimer disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2000;1502(1):1-15.
302. Sherrington R, Rogaev E, Liang Y, Rogaeva E, Levesque G, Ikeda M, et al. Polisnky R1, Wasco W, Da Silva HAR, Haines JL, Pericak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature.375:754-60.
303. Kelleher RJ, 3rdShen J. Presenilin-1 mutations and Alzheimer's disease. Proc Natl Acad Sci U S A. 2017;114(4):629-31.
304. Restrepo LJ, DePew AT, Moese ER, Tymanskyj SR, Parisi MJ, Aimino MA, et al. γ-secretase promotes Drosophila postsynaptic development through the cleavage of a Wnt receptor. Developmental Cell. 2022.
305. Monacelli F, Martella L, Parodi MN, Odetti P, Fanelli FTabaton M. Frontal variant of Alzheimer’s disease: a report of a novel PSEN1 mutation. Journal of Alzheimer's Disease. 2019;70(1):11-15.
306. Duff K, Eckman C, Zehr C, Yu X, Prada C-M, Perez-Tur J, et al. Increased amyloid-β42 (43) in brains of mice expressing mutant presenilin 1. Nature. 1996;383(6602):710-13.
307. Hardy JSelkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. science. 2002;297(5580):353-56.
308. Selkoe DJHardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine. 2016;8(6):595-608.
309. Shen JKelleher III RJ. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proceedings of the National Academy of Sciences. 2007;104(2):403-09.
310. Wines-Samuelson M, Schulte EC, Smith MJ, Aoki C, Liu X, Kelleher III RJ, et al. Characterization of age-dependent and progressive cortical neuronal degeneration in presenilin conditional mutant mice. PLoS One. 2010;5(4):e10195.
311. Watanabe H, Xia D, Kanekiyo T, Kelleher RJShen J. Familial frontotemporal dementia-associated presenilin-1 c. 548G> T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice. Journal of Neuroscience. 2012;32(15):5085-96.
312. Saura CA, Choi S-Y, Beglopoulos V, Malkani S, Zhang D, Rao BS, et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004;42(1):23-36.
313. Xia D, Watanabe H, Wu B, Lee SH, Li Y, Tsvetkov E, et al. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015;85(5):967-81.
314. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995;269(5226):973-77.
315. Cai Y, An SSKim S. Mutations in presenilin 2 and its implications in Alzheimer's disease and other dementia-associated disorders. Clin Interv Aging. 2015;10:1163-72.
316. Rademakers R, Cruts MVan Broeckhoven C. Genetics of early-onset Alzheimer dementia. TheScientificWorldJournal. 2003;3:497-519.
317. Annaert WG, Levesque L, Craessaerts K, Dierinck I, Snellings G, Westaway D, et al. Presenilin 1 controls γ-secretase processing of amyloid precursor protein in pre-Golgi compartments of hippocampal neurons. The Journal of cell biology. 1999;147(2):277-94.
318. Leissring MA, Yamasaki TR, Wasco W, Buxbaum JD, Parker ILaFerla FM. Calsenilin reverses presenilin-mediated enhancement of calcium signaling. Proceedings of the National Academy of Sciences. 2000;97(15):8590-93.
319. Leissring MA, LaFerla FM, Callamaras NParker I. Subcellular mechanisms of presenilin-mediated enhancement of calcium signaling. Neurobiology of disease. 2001;8(3):469-78.
320. Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature medicine. 1997;3(1):67-72.
321. Goldgaber D, Lerman MI, McBride OW, Saffiotti UGajdusek DC. Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer's disease. Science. 1987;235(4791):877-80.
322. Müller UCZheng H. Physiological functions of APP family proteins. Cold Spring Harb Perspect Med. 2012;2(2):a006288.
323. Tharp WGSarkar IN. Origins of amyloid-β. BMC Genomics. 2013;14(1):290.
324. Dahms SO, Hoefgen S, Roeser D, Schlott B, Gührs KHThan ME. Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2010;107(12):5381-6.
325. Guénette S, Strecker PKins S. APP protein family signaling at the synapse: insights from intracellular APP-binding proteins. Frontiers in Molecular Neuroscience. 2017;10:87.
326. Nikolaev A, McLaughlin T, O'Leary DDTessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009;457(7232):981-9.
327. Zheng HKoo EH. Biology and pathophysiology of the amyloid precursor protein. Molecular Neurodegeneration. 2011;6(1):27.
328. Haass C, Hung AY, Selkoe DJTeplow DB. Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. Journal of Biological Chemistry. 1994;269(26):17741-48.
329. Suzuki N, Cheung TT, Cai X-D, Odaka A, Otvos Jr L, Eckman C, et al. An increased percentage of long amyloid β protein secreted by familial amyloid β protein precursor (βAPP717) mutants. Science. 1994;264(5163):1336-40.
330. Tcw JGoate AM. Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease. Cold Spring Harb Perspect Med. 2017;7(6).
331. Busciglio J, Gabuzda DH, Matsudaira PYankner BA. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proceedings of the National Academy of Sciences. 1993;90(5):2092-96.
332. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, et al. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid. Nature genetics. 1992;1(5):345-47.
333. Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, et al. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990;248(4959):1124-26.
334. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, et al. The'Arctic'APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation. Nature neuroscience. 2001;4(9):887-93.
335. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends in neurosciences. 1997;20(4):154-59.
336. Giaccone G, Morbin M, Moda F, Botta M, Mazzoleni G, Uggetti A, et al. Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features. Acta neuropathologica. 2010;120:803-12.
337. Maloney JA, Bainbridge T, Gustafson A, Zhang S, Kyauk R, Steiner P, et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. Journal of Biological Chemistry. 2014;289(45):30990-1000.
338. Jonsson T, Atwal JK, Steinberg S, Sna
IssueVol 8, No 2 (2025); in press QRcode
SectionReview Article
DOI https://doi.org/10.18502/igj.v8i2.17998
Keywords
Alzheimer’s Disease (AD) Pro-Inflammatory Cytokine Neuroinflammation Metabolism

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Rafiyan M, Mojtahedi H. Role of Neuroinflammation in Alzheimer’s Disease (AD). Immunol Genet J. 2025;8(2).