Top

Published in:

Open Access 01-12-2024 | Alzheimer's Disease | Research

iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype

Authors: Michael A. Sullivan, Samuel D. Lane, André D. J. McKenzie, Sarah R. Ball, Margaret Sunde, G. Gregory Neely, Cesar L. Moreno, Alexandra Maximova, Eryn L. Werry, Michael Kassiou

Published in: Journal of Neuroinflammation | Issue 1/2024

Abstract

Background

Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer’s disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells.

Methods

iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ₄₂ and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ₄₂.

Results

AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ₄₂ while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia.

Conclusion

Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a ‘primed’ phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ₄₂ production and phagocytosis.

Available only for authorised users

Bertram L, Tanzi RE. Genome-wide association studies in Alzheimer’s disease. Hum Mol Genet. 2009;18(R2):R137–45.PubMedPubMedCentralCrossRef

D’Avanzo C, Aronson J, Kim YH, Choi SH, Tanzi RE, Kim DY. Alzheimer’s in 3D culture: challenges and perspectives. BioEssays. 2015;37(10):1139–48.PubMedPubMedCentralCrossRef

De Jonghe C, Esselens C, Kumar-Singh S, Craessaerts K, Serneels S, Checler F, et al. Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability. Hum Mol Genet. 2001;10(16):1665–71.PubMedCrossRef

Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81(2):741–66.PubMedCrossRef

Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, et al. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010;133(Pt 4):1143–54.PubMedPubMedCentralCrossRef

Ortiz-Virumbrales M, Moreno CL, Kruglikov I, Marazuela P, Sproul A, Jacob S, et al. CRISPR/Cas9-Correctable mutation-related molecular and physiological phenotypes in iPSC-derived Alzheimer’s PSEN2 N141I neurons. Acta Neuropathol Commun. 2017;5(1):1–20.CrossRef

Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell. 2005;120(4):545–55.PubMedCrossRef

Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8.PubMedPubMedCentralCrossRef

Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358(9280):461–7.PubMedCrossRef

10.

Hamelin L, Lagarde J, Dorothee G, Leroy C, Labit M, Comley RA, et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016;139(Pt 4):1252–64.PubMedCrossRef

11.

Funato H, Yoshimura M, Yamazaki T, Saido TC, Ito Y, Yokofujita J, et al. Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40-positive diffuse plaques in the aged human brain. Am J Pathol. 1998;152(4):983–92.PubMedPubMedCentral

12.

Kamphuis W, Middeldorp J, Kooijman L, Sluijs JA, Kooi EJ, Moeton M, et al. Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer’s disease. Neurobiol Aging. 2014;35(3):492–510.PubMedCrossRef

13.

Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971(2):197–209.PubMedCrossRef

14.

Senitz D, Reichenbach A, Smith TG Jr. Surface complexity of human neocortical astrocytic cells: changes with development, aging, and dementia. J Hirnforsch. 1995;36(4):531–7.PubMed

15.

Dandrea MR, Reiser PA, Gumula NA, Hertzog BM, Andrade-Gordon P. Application of triple immunohistochemistry to characterize amyloid plaque-associated inflammation in brains with Alzheimer’s disease. Biotech Histochem. 2001;76(2):97–106.PubMedCrossRef

16.

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(3):135–8.PubMedCrossRef

17.

Shao Y, Gearing M, Mirra SS. Astrocyte-apolipoprotein E associations in senile plaques in Alzheimer disease and vascular lesions: a regional immunohistochemical study. J Neuropathol Exp Neurol. 1997;56(4):376–81.PubMedCrossRef

18.

Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol. 2017;133(2):155–75.PubMedCrossRef

19.

Sloan SA, Darmanis S, Huber N, Khan TA, Birey F, Caneda C, et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron. 2017;95(4):779-90.e6.PubMedPubMedCentralCrossRef

20.

Camp JG, Badsha F, Florio M, Kanton S, Gerber T, Wilsch-Brauninger M, et al. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A. 2015;112(51):15672–7.PubMedPubMedCentralCrossRef

21.

Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron. 2017;94(2):278-93.e9.PubMedPubMedCentralCrossRef

22.

McQuade A, Coburn M, Tu CH, Hasselmann J, Davtyan H, Blurton-Jones M. Development and validation of a simplified method to generate human microglia from pluripotent stem cells. Mol Neurodegener. 2018;13(1):67.PubMedPubMedCentralCrossRef

23.

Tcw J, Wang M, Pimenova AA, Bowles KR, Hartley BJ, Lacin E, et al. An efficient platform for astrocyte differentiation from human induced pluripotent stem cells. Stem Cell Reports. 2017;9(2):600–14.PubMedPubMedCentralCrossRef

24.

Jones VC, Atkinson-Dell R, Verkhratsky A, Mohamet L. Aberrant iPSC-derived human astrocytes in Alzheimer’s disease. Cell Death Dis. 2017;8(3): e2696.PubMedPubMedCentralCrossRef

25.

Konttinen H, Cabral-da-Silva MEC, Ohtonen S, Wojciechowski S, Shakirzyanova A, Caligola S, et al. PSEN1DeltaE9, APPswe, and APOE4 confer disparate phenotypes in human iPSC-derived microglia. Stem Cell Rep. 2019;13(4):669–83.CrossRef

26.

Konttinen H, Gureviciene I, Oksanen M, Grubman A, Loppi S, Huuskonen MT, et al. PPARbeta/delta-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1DeltaE9 astrocytes. Glia. 2019;67(1):146–59.PubMedCrossRef

27.

Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen S, Gubert Olive M, et al. PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease. Stem Cell Reports. 2017;9(6):1885–97.PubMedPubMedCentralCrossRef

28.

Park J, Wetzel I, Marriott I, Dreau D, D’Avanzo C, Kim DY, et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci. 2018;21(7):941–51.PubMedPubMedCentralCrossRef

29.

Guttikonda SR, Sikkema L, Tchieu J, Saurat N, Walsh RM, Harschnitz O, et al. Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer’s disease. Nat Neurosci. 2021;24(3):343–54.PubMedPubMedCentralCrossRef

30.

Xu M, Zhang L, Liu G, Jiang N, Zhou W, Zhang Y. Pathological changes in Alzheimer’s disease analyzed using induced pluripotent stem cell-derived human microglia-like cells. J Alzheimers Dis. 2019;67(1):357–68.PubMedCrossRef

31.

Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron. 2018;98(6):1141-54.e7.PubMedPubMedCentralCrossRef

32.

Walsh DM, Thulin E, Minogue AM, Gustavsson N, Pang E, Teplow DB, et al. A facile method for expression and purification of the Alzheimer’s disease-associated amyloid beta-peptide. FEBS J. 2009;276(5):1266–81.PubMedPubMedCentralCrossRef

33.

Tian C, Liu Q, Ma K, Wang Y, Chen Q, Ambroz R, et al. Characterization of induced neural progenitors from skin fibroblasts by a novel combination of defined factors. Sci Rep. 2013;3:1345.PubMedPubMedCentralCrossRef

34.

Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957–67.PubMedCrossRef

35.

Ao Z, Cai H, Wu Z, Song S, Karahan H, Kim B, et al. Tubular human brain organoids to model microglia-mediated neuroinflammation. Lab Chip. 2021;21(14):2751–62.PubMedPubMedCentralCrossRef

36.

Liu W, Taso O, Wang R, Bayram S, Graham AC, Garcia-Reitboeck P, et al. Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions. Hum Mol Genet. 2020;29(19):3224–48.PubMedPubMedCentralCrossRef

37.

Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res. 1998;57(1):1–9.PubMedCrossRef

38.

Franco-Bocanegra DK, Gourari Y, McAuley C, Chatelet DS, Johnston DA, Nicoll JAR, et al. Microglial morphology in Alzheimer’s disease and after Abeta immunotherapy. Sci Rep. 2021;11(1):15955.PubMedPubMedCentralCrossRef

39.

Davies DS, Ma J, Jegathees T, Goldsbury C. Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol. 2017;27(6):795–808.PubMedCrossRef

40.

Young K, Morrison H. Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using imageJ. J Vis Exp. 2018;136:e57648.

41.

Brandenburg LO, Konrad M, Wruck CJ, Koch T, Lucius R, Pufe T. Functional and physical interactions between formyl-peptide-receptors and scavenger receptor MARCO and their involvement in amyloid beta 1–42-induced signal transduction in glial cells. J Neurochem. 2010;113(3):749–60.PubMedCrossRef

42.

Xu X, Lei Y, Luo J, Wang J, Zhang S, Yang XJ, et al. Prevention of beta-amyloid induced toxicity in human iPS cell-derived neurons by inhibition of Cyclin-dependent kinases and associated cell cycle events. Stem Cell Res. 2013;10(2):213–27.PubMedCrossRef

43.

Ferreira A, Sinjoanu RC, Nicholson A, Kleinschmidt S. Abeta toxicity in primary cultured neurons. Methods Mol Biol. 2011;670:141–53.PubMedCrossRef

44.

Veeraraghavalu K, Zhang C, Zhang X, Tanzi RE, Sisodia SS. Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of beta-amyloid by cells other than excitatory neurons. J Neurosci. 2014;34(10):3668–73.PubMedPubMedCentralCrossRef

45.

McQuade A, Kang YJ, Hasselmann J, Jairaman A, Sotelo A, Coburn M, et al. Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease. Nat Commun. 2020;11(1):5370.PubMedPubMedCentralCrossRef

46.

Bottcher C, Schlickeiser S, Sneeboer MAM, Kunkel D, Knop A, Paza E, et al. Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nat Neurosci. 2019;22(1):78–90.PubMedCrossRef

47.

Carpenter AF, Carpenter PW, Markesbery WR. Morphometric analysis of microglia in Alzheimer’s disease. J Neuropathol Exp Neurol. 1993;52(6):601–8.PubMedCrossRef

48.

Vehmas AK, Kawas CH, Stewart WF, Troncoso JC. Immune reactive cells in senile plaques and cognitive decline in Alzheimer’s disease. Neurobiol Aging. 2003;24(2):321–31.PubMedCrossRef

49.

Beauquis J, Pavia P, Pomilio C, Vinuesa A, Podlutskaya N, Galvan V, et al. Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp Neurol. 2013;239:28–37.PubMedCrossRef

50.

Kulijewicz-Nawrot M, Verkhratsky A, Chvatal A, Sykova E, Rodriguez JJ. Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J Anat. 2012;221(3):252–62.PubMedPubMedCentralCrossRef

51.

Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia. 2010;58(7):831–8.PubMedCrossRef

52.

Hyvarinen T, Hagman S, Ristola M, Sukki L, Veijula K, Kreutzer J, et al. Co-stimulation with IL-1beta and TNF-alpha induces an inflammatory reactive astrocyte phenotype with neurosupportive characteristics in a human pluripotent stem cell model system. Sci Rep. 2019;9(1):16944.PubMedPubMedCentralCrossRef

53.

Escartin C, Guillemaud O, Carrillo-de Sauvage MA. Questions and (some) answers on reactive astrocytes. Glia. 2019;67(12):2221–47.PubMedCrossRef

54.

Simpson JE, Ince PG, Lace G, Forster G, Shaw PJ, Matthews F, et al. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol Aging. 2010;31(4):578–90.PubMedCrossRef

55.

Kashon ML, Ross GW, O'Callaghan JP, Miller DB, Petrovitch H, Burchfiel CM, et al. Associations of cortical astrogliosis with cognitive performance and dementia status. J Alzheimers Dis. 2004;6(6):595–604; discussion 73–81.

56.

Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989;86(19):7611–5.PubMedPubMedCentralCrossRef

57.

Mrak RE, Sheng JG, Griffin WS. Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’s disease. J Neuropathol Exp Neurol. 1996;55(3):273–9.PubMedCrossRef

58.

Sheng JG, Mrak RE, Griffin WS. S100 beta protein expression in Alzheimer disease: potential role in the pathogenesis of neuritic plaques. J Neurosci Res. 1994;39(4):398–404.PubMedCrossRef

59.

Marshak DR, Pesce SA, Stanley LC, Griffin WS. Increased S100 beta neurotrophic activity in Alzheimer’s disease temporal lobe. Neurobiol Aging. 1992;13(1):1–7.PubMedCrossRef

60.

Brozzi F, Arcuri C, Giambanco I, Donato R. S100B protein regulates astrocyte shape and migration via interaction with Src kinase: implications for astrocyte development, activation and tumor growth. J Biol Chem. 2009;284(13):8797–811.PubMedPubMedCentralCrossRef

61.

Torres-Platas SG, Comeau S, Rachalski A, Bo GD, Cruceanu C, Turecki G, et al. Morphometric characterization of microglial phenotypes in human cerebral cortex. J Neuroinflammation. 2014;11:12.PubMedPubMedCentralCrossRef

62.

Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–68.PubMedPubMedCentralCrossRef

63.

Salobrar-Garcia E, Rodrigues-Neves AC, Ramirez AI, de Hoz R, Fernandez-Albarral JA, Lopez-Cuenca I, et al. Microglial activation in the retina of a triple-transgenic Alzheimer’s disease mouse model (3xTg-AD). Int J Mol Sci. 2020;21(3):816.PubMedPubMedCentralCrossRef

64.

Baron R, Babcock AA, Nemirovsky A, Finsen B, Monsonego A. Accelerated microglial pathology is associated with Abeta plaques in mouse models of Alzheimer’s disease. Aging Cell. 2014;13(4):584–95.PubMedPubMedCentralCrossRef

65.

Leyh J, Paeschke S, Mages B, Michalski D, Nowicki M, Bechmann I, et al. Classification of Microglial Morphological Phenotypes Using Machine Learning. Front Cell Neurosci. 2021;15: 701673.PubMedPubMedCentralCrossRef

66.

Nam H, Lee Y, Kim B, Lee JW, Hwang S, An HK, et al. Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBalpha. Nat Commun. 2022;13(1):1972.PubMedPubMedCentralCrossRef

67.

Fung S, Smith CL, Prater KE, Case A, Green K, Osnis L, et al. Early-onset familial Alzheimer disease variant PSEN2 N141I heterozygosity is associated with altered microglia phenotype. J Alzheimers Dis. 2020;77(2):675–88.PubMedPubMedCentralCrossRef

68.

Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:575–90.PubMedCrossRef

69.

Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16(6):358–72.PubMedCrossRef

70.

Grehan S, Tse E, Taylor JM. Two distal downstream enhancers direct expression of the human apolipoprotein E gene to astrocytes in the brain. J Neurosci. 2001;21(3):812–22.PubMedPubMedCentralCrossRef

71.

Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18.PubMedPubMedCentralCrossRef

72.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3.PubMedCrossRef

73.

den Hartigh LJ, Altman R, Hutchinson R, Petrlova J, Budamagunta MS, Tetali SD, et al. Postprandial apoE isoform and conformational changes associated with VLDL lipolysis products modulate monocyte inflammation. PLoS ONE. 2012;7(11): e50513.CrossRef

74.

Hatters DM, Budamagunta MS, Voss JC, Weisgraber KH. Modulation of apolipoprotein E structure by domain interaction: differences in lipid-bound and lipid-free forms. J Biol Chem. 2005;280(40):34288–95.PubMedCrossRef

75.

Maezawa I, Maeda N, Montine TJ, Montine KS. Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice. J Neuroinflammation. 2006;3:10.PubMedPubMedCentralCrossRef

76.

Ophir G, Meilin S, Efrati M, Chapman J, Karussis D, Roses A, et al. Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice. Neurobiol Dis. 2003;12(1):56–64.PubMedCrossRef

77.

Fraga VG, Magalhaes CA, Loures CMG, de Souza LC, Guimaraes HC, Zauli DAG, et al. Inflammatory and pro-resolving mediators in frontotemporal dementia and Alzheimer’s disease. Neuroscience. 2019;421:123–35.PubMedCrossRef

78.

Ehrlich LC, Hu S, Sheng WS, Sutton RL, Rockswold GL, Peterson PK, et al. Cytokine regulation of human microglial cell IL-8 production. J Immunol. 1998;160(4):1944–8.PubMedCrossRef

79.

Araujo DM, Cotman CW. Trophic effects of interleukin-4, -7 and -8 on hippocampal neuronal cultures: potential involvement of glial-derived factors. Brain Res. 1993;600(1):49–55.PubMedCrossRef

80.

Akiyama H, Kawamata T, Yamada T, Tooyama I, Ishii T, McGeer PL. Expression of intercellular adhesion molecule (ICAM)-1 by a subset of astrocytes in Alzheimer disease and some other degenerative neurological disorders. Acta Neuropathol. 1993;85(6):628–34.PubMedCrossRef

81.

Verbeek MM, Otte-Holler I, Westphal JR, Wesseling P, Ruiter DJ, de Waal RM. Accumulation of intercellular adhesion molecule-1 in senile plaques in brain tissue of patients with Alzheimer’s disease. Am J Pathol. 1994;144(1):104–16.PubMedPubMedCentral

82.

Rozemuller JM, Eikelenboom P, Pals ST, Stam FC. Microglial cells around amyloid plaques in Alzheimer’s disease express leucocyte adhesion molecules of the LFA-1 family. Neurosci Lett. 1989;101(3):288–92.PubMedCrossRef

83.

Noe CR, Noe-Letschnig M, Handschuh P, Noe CA, Lanzenberger R. Dysfunction of the Blood-Brain Barrier-A Key Step in Neurodegeneration and Dementia. Front Aging Neurosci. 2020;12:185.PubMedPubMedCentralCrossRef

84.

Nielsen HM, Londos E, Minthon L, Janciauskiene SM. Soluble adhesion molecules and angiotensin-converting enzyme in dementia. Neurobiol Dis. 2007;26(1):27–35.PubMedCrossRef

85.

Clark PR, Manes TD, Pober JS, Kluger MS. Increased ICAM-1 expression causes endothelial cell leakiness, cytoskeletal reorganization and junctional alterations. J Invest Dermatol. 2007;127(4):762–74.PubMedCrossRef

86.

Rentzos M, Michalopoulou M, Nikolaou C, Cambouri C, Rombos A, Dimitrakopoulos A, et al. The role of soluble intercellular adhesion molecules in neurodegenerative disorders. J Neurol Sci. 2005;228(2):129–35.PubMedCrossRef

87.

Janelidze S, Mattsson N, Stomrud E, Lindberg O, Palmqvist S, Zetterberg H, et al. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurology. 2018;91(9):e867–77.PubMedPubMedCentralCrossRef

88.

Perez-Nievas BG, Johnson L, Beltran-Lobo P, Hughes MM, Gammallieri L, Tarsitano F, et al. Astrocytic C-X-C motif chemokine ligand-1 mediates beta-amyloid-induced synaptotoxicity. J Neuroinflammation. 2021;18(1):306.PubMedPubMedCentralCrossRef

89.

Prinz M, Hanisch UK. Murine microglial cells produce and respond to interleukin-18. J Neurochem. 1999;72(5):2215–8.PubMedCrossRef

90.

Nasiri E, Sankowski R, Dietrich H, Oikonomidi A, Huerta PT, Popp J, et al. Key role of MIF-related neuroinflammation in neurodegeneration and cognitive impairment in Alzheimer’s disease. Mol Med. 2020;26(1):34.PubMedPubMedCentralCrossRef

91.

Ojala J, Alafuzoff I, Herukka SK, 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(2):198–209.PubMedCrossRef

92.

Srinivasan K, Friedman BA, Etxeberria A, Huntley MA, van der Brug MP, Foreman O, et al. Alzheimer’s patient microglia exhibit enhanced aging and unique transcriptional activation. Cell Rep. 2020;31(13): 107843.PubMedPubMedCentralCrossRef

93.

Monaco G, van Dam S, Casal Novo Ribeiro JL, Larbi A, de Magalhaes JP. A comparison of human and mouse gene co-expression networks reveals conservation and divergence at the tissue, pathway and disease levels. BMC Evol Biol. 2015;15:259.PubMedPubMedCentralCrossRef

94.

Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330(6012):1774.PubMedPubMedCentralCrossRef

95.

Reich M, Paris I, Ebeling M, Dahm N, Schweitzer C, Reinhardt D, et al. Alzheimer’s risk gene TREM2 determines functional properties of new type of human iPSC-derived microglia. Front Immunol. 2020;11: 617860.PubMedCrossRef

96.

Hall-Roberts H, Agarwal D, Obst J, Smith TB, Monzon-Sandoval J, Di Daniel E, et al. TREM2 Alzheimer’s variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages. Alzheimers Res Ther. 2020;12(1):151.PubMedPubMedCentralCrossRef

Title: iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype
Authors: Michael A. Sullivan
Samuel D. Lane
André D. J. McKenzie
Sarah R. Ball
Margaret Sunde
G. Gregory Neely
Cesar L. Moreno
Alexandra Maximova
Eryn L. Werry
Michael Kassiou
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Alzheimer's Disease
Alzheimer's Disease
Cytokines
Published in: Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02951-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

iPSC-derived PSEN2 (N141I) astrocytes and microglia exhibit a primed inflammatory phenotype

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2024

Impaired cerebral microvascular endothelial cells integrity due to elevated dopamine in myasthenic model

Deletion of Slc9a1 in Cx3cr1+ cells stimulated microglial subcluster CREB1 signaling and microglia-oligodendrocyte crosstalk

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice

Identification of female-enriched and disease-associated microglia (FDAMic) contributes to sexual dimorphism in late-onset Alzheimer’s disease

Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain

SPOCK2 modulates neuropathic pain by interacting with MT1-MMP to regulate astrocytic MMP-2 activation in rats with chronic constriction injury