Genome-wide Identification of Murine Interferon Genes in Microglial-mediated Neuroinflammation in Alzheimer's Disease

Overview

Journal J Neuroimmunol

Specialty Neurology

Date 2023 Jan 28

PMID 36708632

Authors

Daniel C Shippy

Tyler K Ulland

Affiliations

Soon will be listed here.

Abstract

Interferons play a major role in microglial-mediated neuroinflammation in Alzheimer's disease (AD). We investigated the interferon transcriptome (AD versus non-AD) using N9 and murine microglia. We identified 64 interferon-related differentially expressed genes (DEG) in LPS-stimulated N9 microglia versus control cells, 26 DEG in microglia from 5XFAD versus wild-type mice, with 13 DEG common to both datasets. Network analyses identified potential key mediators (Cxcl10, Ifit3) of the interferon response in AD. Gene-drug interaction analysis identified therapeutics targeting interferon-related genes. These data characterize the microglial interferon response in AD, providing new targets and therapeutics directed towards interferon-related neuroinflammation in AD.

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References

Nikodemova M, Watters J . Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice. Neuroscience. 2011; 190:67-74. PMC: 3156380. DOI: 10.1016/j.neuroscience.2011.06.006. View

Deczkowska A, Baruch K, Schwartz M . Type I/II Interferon Balance in the Regulation of Brain Physiology and Pathology. Trends Immunol. 2016; 37(3):181-192. DOI: 10.1016/j.it.2016.01.006. View

Toshchakov V, Jones B, Perera P, Thomas K, Cody M, Zhang S . TLR4, but not TLR2, mediates IFN-beta-induced STAT1alpha/beta-dependent gene expression in macrophages. Nat Immunol. 2002; 3(4):392-8. DOI: 10.1038/ni774. View

Cotto K, Wagner A, Feng Y, Kiwala S, Coffman A, Spies G . DGIdb 3.0: a redesign and expansion of the drug-gene interaction database. Nucleic Acids Res. 2017; 46(D1):D1068-D1073. PMC: 5888642. DOI: 10.1093/nar/gkx1143. View

Zhang X, Tong T, Chang A, Ang T, Tao Q, Auerbach S . Midlife lipid and glucose levels are associated with Alzheimer's disease. Alzheimers Dement. 2022; 19(1):181-193. PMC: 10078665. DOI: 10.1002/alz.12641. View

Hsu Y, Shi S, Wu W, Ho L, Lai J . Protective roles of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in dengue virus infection of human lung epithelial cells. PLoS One. 2013; 8(11):e79518. PMC: 3817122. DOI: 10.1371/journal.pone.0079518. View

Guo B, Jiang T, Wu F, Ni H, Ye J, Wu X . LncRNA RP5-998N21.4 promotes immune defense through upregulation of IFIT2 and IFIT3 in schizophrenia. Schizophrenia (Heidelb). 2022; 8(1):11. PMC: 8888552. DOI: 10.1038/s41537-021-00195-8. View

Correa J, Starling D, Teixeira A, Caramelli P, Silva T . Chemokines in CSF of Alzheimer's disease patients. Arq Neuropsiquiatr. 2011; 69(3):455-9. DOI: 10.1590/s0004-282x2011000400009. View

De Strooper B, Karran E . The Cellular Phase of Alzheimer's Disease. Cell. 2016; 164(4):603-15. DOI: 10.1016/j.cell.2015.12.056. View

10.

Gitter B, Cox L, Rydel R, May P . Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. Proc Natl Acad Sci U S A. 1995; 92(23):10738-41. PMC: 40687. DOI: 10.1073/pnas.92.23.10738. View

11.

Garwood C, Pooler A, Atherton J, Hanger D, Noble W . Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis. 2011; 2:e167. PMC: 3168992. DOI: 10.1038/cddis.2011.50. View

12.

Spangenberg E, Green K . Inflammation in Alzheimer's disease: Lessons learned from microglia-depletion models. Brain Behav Immun. 2016; 61:1-11. PMC: 5218993. DOI: 10.1016/j.bbi.2016.07.003. View

13.

Righi M, Mori L, De Libero G, Sironi M, Biondi A, Mantovani A . Monokine production by microglial cell clones. Eur J Immunol. 1989; 19(8):1443-8. DOI: 10.1002/eji.1830190815. View

14.

Fang J, Zhang P, Wang Q, Chiang C, Zhou Y, Hou Y . Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer's disease. Alzheimers Res Ther. 2022; 14(1):7. PMC: 8751379. DOI: 10.1186/s13195-021-00951-z. View

15.

Iqbal K, Grundke-Iqbal I . Alzheimer's disease, a multifactorial disorder seeking multitherapies. Alzheimers Dement. 2010; 6(5):420-4. PMC: 2946155. DOI: 10.1016/j.jalz.2010.04.006. View

16.

Leyns C, Holtzman D . Glial contributions to neurodegeneration in tauopathies. Mol Neurodegener. 2017; 12(1):50. PMC: 5492997. DOI: 10.1186/s13024-017-0192-x. View

17.

Roy E, Chiu G, Li S, Propson N, Kanchi R, Wang B . Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques. Immunity. 2022; 55(5):879-894.e6. PMC: 9109419. DOI: 10.1016/j.immuni.2022.03.018. View

18.

Freshour S, Kiwala S, Cotto K, Coffman A, McMichael J, Song J . Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res. 2020; 49(D1):D1144-D1151. PMC: 7778926. DOI: 10.1093/nar/gkaa1084. View

19.

Liddelow S, Guttenplan K, Clarke L, Bennett F, Bohlen C, Schirmer L . Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017; 541(7638):481-487. PMC: 5404890. DOI: 10.1038/nature21029. View

20.

Wang Y, Cella M, Mallinson K, Ulrich J, Young K, Robinette M . TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015; 160(6):1061-71. PMC: 4477963. DOI: 10.1016/j.cell.2015.01.049. View