Top

Published in:

Open Access 01-12-2020 | Amyotrophic Lateral Sclerosis | Research

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Authors: Frank Zamudio, Anjanet R. Loon, Shayna Smeltzer, Khawla Benyamine, Nanda K. Navalpur Shanmugam, Nicholas J. F. Stewart, Daniel C. Lee, Kevin Nash, Maj-Linda B. Selenica

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

Background

Neuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.

Methods

To investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500 μg/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue.

Results

In the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task.

Conclusions

These results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.

Available only for authorised users

Krecic A, Swanson M. hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol. 1999;11(3).

Ayala YM, Pantano S, D’Ambrogio A, et al. Human, Drosophila, and C. elegans TDP43: nucleic acid binding properties and splicing regulatory function. J Mol Biol. 2005;348(3):575–88. https://doi.org/10.1016/j.jmb.2005.02.038.CrossRefPubMed

Kim SH, Shanware NP, Bowler MJ, Tibbetts RS. Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem. 2010;285(44):34097–105. https://doi.org/10.1074/jbc.M110.154831.CrossRefPubMedPubMedCentral

Chiang PM, Ling J, Jeong YH, Price DL, Aja SM, Wong PC. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci U S A. 2010;107(37):16320–4. https://doi.org/10.1073/pnas.1002176107.CrossRefPubMedPubMedCentral

Abhyankar MM, Urekar C, Reddi PP. A novel CpG-free vertebrate insulator silences the testis-specific SP-10 gene in somatic tissues: Role for TDP-43 in insulator function. J Biol Chem. 2007;282(50):36143–54. https://doi.org/10.1074/jbc.M705811200.CrossRefPubMed

Polymenidou M, Lagier-Tourenne C, Hutt KR, et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci. 2011;14(4):459–68. https://doi.org/10.1038/nn.2779.CrossRefPubMedPubMedCentral

Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351(3):602–11. https://doi.org/10.1016/j.bbrc.2006.10.093.CrossRefPubMed

Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science (80- ). Published online 2006. doi:10.1126/science.1134108.

Rajagopalan V, Pioro EP. Distinct patterns of cortical atrophy in ALS patients with or without dementia: An MRI VBM study. Amyotroph Lateral Scler Front Degener. 2014;15(3-4):216–25. https://doi.org/10.3109/21678421.2014.880179.CrossRef

10.

Steinacker P, Hendrich C, Sperfeld AD, et al. TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol. 2008;65(11):1481–7. https://doi.org/10.1001/archneur.65.11.1481.CrossRefPubMedPubMedCentral

11.

McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J. TDP-43 pathology in Alzheimer’s disease, dementia with Lewy bodies and ageing. Brain Pathol. 2017;27(4):472–9. https://doi.org/10.1111/bpa.12424.CrossRefPubMed

12.

Franceschi C, Campisi J. Chronic inflammation (Inflammaging) and its potential contribution to age-associated diseases. Journals Gerontol - Ser A Biol Sci Med Sci. 2014;69:S4–9. https://doi.org/10.1093/gerona/glu057.CrossRef

13.

Cervellati C, Trentini A, Bosi C, et al. Low-grade systemic inflammation is associated with functional disability in elderly people affected by dementia. GeroScience. 2018;40(1):61–9. https://doi.org/10.1007/s11357-018-0010-6.CrossRefPubMedPubMedCentral

14.

Miller ZA, Sturm VE, Camsari GB, et al. Increased prevalence of autoimmune disease within C9 and FTD/MND cohorts Completing the picture. Neurol Neuroimmunol NeuroInflammation. 2016;3(6). doi:10.1212/NXI.0000000000000301.

15.

Keizman D, Rogowski O, Berliner S, et al. Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 2009;119(6):383–9. https://doi.org/10.1111/j.1600-0404.2008.01112.x.CrossRefPubMed

16.

Hu Y, Cao C, Qin XY, et al. Increased peripheral blood inflammatory cytokine levels in amyotrophic lateral sclerosis: A meta-analysis study. Sci Rep. 2017;7(1). doi:10.1038/s41598-017-09097-1.

17.

Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL. Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol. 2017;74(12):1446–54. https://doi.org/10.1001/jamaneurol.2017.2255.CrossRefPubMedPubMedCentral

18.

Zhang R, Gascon R, Miller RG, et al. Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2005;159(1-2):215–24. https://doi.org/10.1016/j.jneuroim.2004.10.009.CrossRefPubMed

19.

Turner MR, Goldacre R, Ramagopalan S, Talbot K, Goldacre MJ. Autoimmune disease preceding amyotrophic lateral sclerosis: an epidemiologic study. Neurology. 2013;81(14):1222–5. https://doi.org/10.1212/WNL.0b013e3182a6cc13.CrossRefPubMedPubMedCentral

20.

Lee DC, Rizer J, Selenica MLB, et al. LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflammation. 2010;7. https://doi.org/10.1186/1742-2094-7-56.

21.

Lee J, Lee Y, Yuk D, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5(1):37. https://doi.org/10.1186/1742-2094-5-37.CrossRefPubMedPubMedCentral

22.

Correia AS, Patel P, Dutta K, Julien JP. Inflammation induces TDP-43 mislocalization and aggregation. PLoS One. 2015;10(10). doi:10.1371/journal.pone.0140248.

23.

Fontaine SN, Zheng D, Sabbagh JJ, et al. DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative-associated proteins. EMBO J. 2016;35(14):1537–49. https://doi.org/10.15252/embj.201593489.CrossRefPubMedPubMedCentral

24.

Iguchi Y, Eid L, Parent M, et al. Exosome secretion is a key pathway for clearance of pathological TDP-43. Brain. 2016;139(12):3187–201. https://doi.org/10.1093/brain/aww237.CrossRefPubMedPubMedCentral

25.

Carty N, Lee D, Dickey C, et al. Convection-enhanced delivery and systemic mannitol increase gene product distribution of AAV vectors 5, 8, and 9 and increase gene product in the adult mouse brain. J Neurosci Methods. 2010;194(1):144–53. https://doi.org/10.1016/j.jneumeth.2010.10.010.CrossRefPubMedPubMedCentral

26.

Kitazawa M, Oddo S, Yamasaki TR, Green KN, LaFerla FM. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25(39):8843–53. https://doi.org/10.1523/JNEUROSCI.2868-05.2005.CrossRefPubMedPubMedCentral

27.

Yasvoina MV, Genç B, Jara JH, et al. eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. J Neurosci. 2013;33(18):7890–904. https://doi.org/10.1523/JNEUROSCI.2787-12.2013.CrossRefPubMedPubMedCentral

28.

Swarup V, Phaneuf D, Dupré N, et al. Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways. J Exp Med. 2011;208(12):2429–47. https://doi.org/10.1084/jem.20111313.CrossRefPubMedPubMedCentral

29.

Mackenzie IRA, Bigio EH, Ince PG, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61(5):427–34. https://doi.org/10.1002/ana.21147.CrossRefPubMed

30.

Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42(2):145–51. https://doi.org/10.1016/j.cyto.2008.01.006.CrossRefPubMed

31.

Ayala YM, De Conti L, Avendaño-Vázquez SE, et al. TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J. 2011;30(2):277–88. https://doi.org/10.1038/emboj.2010.310.CrossRefPubMed

32.

Li W, Reeb AN, Lin B, et al. Heat shock-induced phosphorylation of TAR DNA-binding protein 43 (TDP-43) by MAPK/ERK kinase regulates TDP-43 function. J Biol Chem. 2017;292(12):5089–100. https://doi.org/10.1074/jbc.M116.753913.CrossRefPubMedPubMedCentral

33.

Wils H, Kleinberger G, Janssens J, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010;107(8):3858–63. https://doi.org/10.1073/pnas.0912417107.CrossRefPubMedPubMedCentral

34.

Tsai KJ, Yang CH, Fang YH, et al. Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med. 2010;207(8):1661–73. https://doi.org/10.1084/jem.20092164.CrossRefPubMedPubMedCentral

35.

Andrade-Moraes CH, Oliveira-Pinto AV, Castro-Fonseca E, et al. Cell number changes in Alzheimer’s disease relate to dementia, not to plaques and tangles. Brain. 2013;136(12):3738–52. https://doi.org/10.1093/brain/awt273.CrossRefPubMedPubMedCentral

36.

Blennow K, Bogdanovic N, Alafuzoff I, Ekman R, Davidsson P. Synaptic pathology in Alzheimer’s disease: relation to severity of dementia, but not to senile plaques, neurofibrillary tangles, or the ApoE4 allele. J Neural Transm. 1996;103(5):603–18. https://doi.org/10.1007/BF01273157.CrossRefPubMed

37.

Woo JAA, Liu T, Trotter C, et al. Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nat Commun. 2017;8(1):1–15. https://doi.org/10.1038/ncomms15558.CrossRef

38.

Jiang T, Handley E, Brizuela M, et al. Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function. DMM Dis Model Mech. 2019;12(5). doi:10.1242/dmm.038109.

39.

Paolicelli RC, Jawaid A, Henstridge CM, et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron. 2017;95(2):297–308.e6. https://doi.org/10.1016/j.neuron.2017.05.037.CrossRefPubMedPubMedCentral

40.

Badshah H, Ali T, Kim MO. Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/NFκB signaling pathway. Sci Rep. 2016;6(1):1–13. https://doi.org/10.1038/srep24493.CrossRef

41.

Sheppard O, Coleman MP, Durrant CS. Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. J Neuroinflammation. 2019;16(1):106. https://doi.org/10.1186/s12974-019-1490-8.CrossRefPubMedPubMedCentral

42.

Xin Y-R, Jiang J-X, Hu Y, et al. The immune system drives synapse loss during lipopolysaccharide-induced learning and memory impairment in mice. Front Aging Neurosci. 2019;11:279. https://doi.org/10.3389/fnagi.2019.00279.CrossRefPubMedPubMedCentral

43.

Jahn R, Südhof TC. Membrane fusion and exocytosis. Annu Rev Biochem. 1999;68(1):863–911. https://doi.org/10.1146/annurev.biochem.68.1.863.CrossRefPubMed

44.

Thammisetty SS, Pedragosa J, Weng YC, Calon F, Planas A, Kriz J. Age-related deregulation of TDP-43 after stroke enhances NF-κB-mediated inflammation and neuronal damage. J Neuroinflammation. 2018;15(1):312. https://doi.org/10.1186/s12974-018-1350-y.CrossRefPubMedPubMedCentral

45.

Cosenza-Nashat MA, Kim MO, Zhao ML, Suh HS, Lee SC. CD45 isoform expression in microglia and inflammatory cells in HIV-1 encephalitis. Brain Pathol. 2006;16(4):256–65. https://doi.org/10.1111/j.1750-3639.2006.00027.x.CrossRefPubMedPubMedCentral

46.

Perlmutter LS, Scott SA, Barrón E, Chui HC. MHC class II-positive microglia in human brain: Association with alzheimer lesions. J Neurosci Res. 1992;33(4):549–58. https://doi.org/10.1002/jnr.490330407.CrossRefPubMed

47.

Nakano A, Harada T, Morikawa S, Kato Y. Expression of leukocyte common antigen (CD45) on various human leukemia/lymphoma cell lines. Pathol Int. 1990;40(2):107–15. https://doi.org/10.1111/j.1440-1827.1990.tb01549.x.CrossRef

48.

Holling TM, Schooten E, Van Den Elsen PJ. Function and regulation of MHC class II molecules in T-lymphocytes: Of mice and men. Hum Immunol. 2004;65(4):282–90. https://doi.org/10.1016/j.humimm.2004.01.005.CrossRefPubMed

49.

Oh J, Shin JS. Molecular mechanism and cellular function of MHCII ubiquitination. Immunol Rev. 2015;266(1):134–44. https://doi.org/10.1111/imr.12303.CrossRefPubMedPubMedCentral

50.

Joly-Amado A, Hunter J, Quadri Z, et al. CCL2 overexpression in the brain promotes glial activation and accelerates tau pathology in a mouse model of tauopathy. Front Immunol. 2020;11:997. https://doi.org/10.3389/fimmu.2020.00997.CrossRefPubMedPubMedCentral

51.

Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK. Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats. J Neuroinflammation. 2011;8. https://doi.org/10.1186/1742-2094-8-41.

52.

Lee PY, Wang J-X, Parisini E, Dascher CC, Nigrovic PA. Ly6 family proteins in neutrophil biology. J Leukoc Biol. 2013;94(4):585–94. https://doi.org/10.1189/jlb.0113014.CrossRefPubMed

53.

Tsuiji H, Inoue I, Takeuchi M, et al. TDP-43 accelerates age-dependent degeneration of interneurons. Sci Rep. 2017;7(1). doi:10.1038/s41598-017-14966-w.

54.

Clark RE, Broadbent NJ, Squire LR. Hippocampus and remote spatial memory in rats. Hippocampus. 2005;15(2):260–72. https://doi.org/10.1002/hipo.20056.CrossRefPubMedPubMedCentral

55.

Cho YH, Kesner RP. Involvement of entorhinal cortex or parietal cortex in long-term spatial discrimination memory in rats: Retrograde amnesia. Behav Neurosci. 1996;110(3):436–42. https://doi.org/10.1037//0735-7044.110.3.436.CrossRefPubMed

56.

Cho YH, Beracochea D, Jaffard R. Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal cortex lesions in mice. J Neurosci. 1993;13(4):1759–66. https://doi.org/10.1523/jneurosci.13-04-01759.1993.CrossRefPubMedPubMedCentral

57.

Ramos JMJ. Short communication: Retrograde amnesia for spatial information: a dissociation between intra and extramaze cues following hippocampus lesions in rats. Eur J Neurosci. 1998;10(10):3295–301. https://doi.org/10.1046/j.1460-9568.1998.00388.x.CrossRefPubMed

58.

Maviel T, Durkin TP, Menzaghi F, Bontempi B. Sites of neocortical reorganization critical for remote spatial memory. Science (80- ). 2004;305(5680):96-99. doi:https://doi.org/10.1126/science.1098180.

59.

Broadbent NJ, Squire LR, Clark RE. Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests. Learn Mem. 2006;13(2):187–91. https://doi.org/10.1101/lm.134706.CrossRefPubMedPubMedCentral

60.

Hok V, Save E, Lenck-Santini PP, Poucet B. Coding for spatial goals in the prelimbic/infralimbic area of the rat frontal cortex. Proc Natl Acad Sci U S A. 2005;102(12):4602–7. https://doi.org/10.1073/pnas.0407332102.CrossRefPubMedPubMedCentral

61.

Basu J, Siegelbaum SA. The corticohippocampal circuit, synaptic plasticity, and memory. Cold Spring Harb Perspect Biol. 2015;7(11):a021733. https://doi.org/10.1101/cshperspect.a021733.CrossRefPubMedPubMedCentral

62.

Genzel L, Battaglia FP. Cortico-hippocampal circuits for memory consolidation: the role of the prefrontal cortex. In: Springer, Cham; 2017:265-281. doi:10.1007/978-3-319-45066-7_16.

63.

De Bruin JPC, Swinkels WAM, De Brabander JM. Response learning of rats in a Morris water maze: involvement of the medial prefrontal cortex. Behav Brain Res. 1997;85(1):47–55. https://doi.org/10.1016/S0166-4328(96)00163-5.CrossRefPubMed

64.

De Bruin JPC, Moita MP, De Brabander HM, Joosten RNJMA. Place and response learning of rats in a Morris water maze: differential effects of fimbria fornix and medial prefrontal cortex lesions. Neurobiol Learn Mem. 2001;75(2):164–78. https://doi.org/10.1006/nlme.2000.3962.CrossRefPubMed

65.

Kolb B, Sutherland RJ, Whishaw IQ. A comparison of the contributions of the frontal and parietal association cortex to spatial localization in rats. Behav Neurosci. 1983;97(1):13–27. https://doi.org/10.1037/0735-7044.97.1.13.CrossRefPubMed

66.

Sang Jo Y, Eun HP, Il HK, et al. The medial prefrontal cortex is involved in spatial memory retrieval under partial-cue conditions. J Neurosci. 2007;27(49):13567–78. https://doi.org/10.1523/JNEUROSCI.3589-07.2007.CrossRef

67.

Save E, Poucet B, Foreman N, Thinus-Blanc C. The contribution of the associative parietal cortex and hippocampus to spatial processing in rodents. Psychobiology. 1998;26(2):153–61. https://doi.org/10.3758/BF03330603.CrossRef

68.

Woolley DG, Laeremans A, Gantois I, et al. Homologous involvement of striatum and prefrontal cortex in rodent and human water maze learning. Proc Natl Acad Sci U S A. 2013;110(8):3131–6. https://doi.org/10.1073/pnas.1217832110.CrossRefPubMedPubMedCentral

69.

Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019;142(6):1503–27. https://doi.org/10.1093/brain/awz099.CrossRefPubMedPubMedCentral

70.

Hess DC, Bhutwala T, Sheppard JC, Zhao W, Smith J. ICAM-1 expression on human brain microvascular endothelial cells. Neurosci Lett. 1994;168(1-2):201–4. https://doi.org/10.1016/0304-3940(94)90450-2.CrossRefPubMed

71.

Lutz SE, Smith JR, Kim DH, et al. Caveolin1 is required for Th1 cell infiltration, but not tight junction remodeling, at the blood-brain barrier in autoimmune neuroinflammation. Cell Rep. 2017;21(8):2104–17. https://doi.org/10.1016/j.celrep.2017.10.094.CrossRefPubMedPubMedCentral

72.

Haarmann A, Nowak E, Deiß A, et al. Soluble VCAM-1 impairs human brain endothelial barrier integrity via integrin α-4-transduced outside-in signalling. Acta Neuropathol. 2015;129(5):639–52. https://doi.org/10.1007/s00401-015-1417-0.CrossRefPubMedPubMedCentral

73.

Blair LJ, Frauen HD, Zhang B, et al. Tau depletion prevents progressive blood-brain barrier damage in a mouse model of tauopathy. Acta Neuropathol Commun. 2015;3:8. https://doi.org/10.1186/s40478-015-0186-2.CrossRefPubMedPubMedCentral

74.

Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178–201. https://doi.org/10.1016/j.neuron.2008.01.003.CrossRefPubMed

75.

Daneman R. The blood-brain barrier in health and disease. Ann Neurol. 2012;72(5):648–72. https://doi.org/10.1002/ana.23648.CrossRefPubMed

76.

Banks WA, Robinson SM. Minimal penetration of lipopolysaccharide across the murine blood-brain barrier. Brain Behav Immun. 2010;24(1):102–9. https://doi.org/10.1016/j.bbi.2009.09.001.CrossRefPubMed

77.

Liverani E, Rico MC, Yaratha L, Tsygankov AY, Kilpatrick LE, Kunapuli SP. LPS-induced systemic inflammation is more severe in P2Y 12 null mice. J Leukoc Biol. 2014;95(2):313–23. https://doi.org/10.1189/jlb.1012518.CrossRefPubMedPubMedCentral

78.

Laurent C, Dorothée G, Hunot S, et al. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain. Published online 2017. doi:https://doi.org/10.1093/brain/aww270.

79.

Varvel NH, Neher JJ, Bosch A, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc Natl Acad Sci U S A. 2016;113(38):E5665–74. https://doi.org/10.1073/pnas.1604263113.CrossRefPubMedPubMedCentral

80.

Stranahan AM, Hao S, Dey A, Yu X, Baban B. Blood-brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice. J Cereb Blood Flow Metab. 2016;36(12):2108–21. https://doi.org/10.1177/0271678X16642233.CrossRefPubMedPubMedCentral

81.

Crittenden M, Gough M, Harrington K, Olivier K, Thompson J, Vile RG. Expression of inflammatory chemokines combined with local tumor destruction enhances tumor regression and long-term immunity. Cancer Res. 2003;63(17):5505–12 Accessed November 20, 2019. http://www.ncbi.nlm.nih.gov/pubmed/14500387.PubMed

82.

Palmer C, Roberts RL, Young PI. Timing of neutrophil depletion influences long-term neuroprotection in neonatal rat hypoxic-ischemic brain injury. Pediatr Res. Published online 2004. doi:https://doi.org/10.1203/01.PDR.0000113546.03897.FC.

83.

Werner C, Engelhard K. Pathophysiology of traumatic brain injury. Br J Anaesth. Published online 2007. doi:https://doi.org/10.1093/bja/aem131.

84.

Zenaro E, Pietronigro E, Bianca V Della, et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med. Published online 2015. doi:10.1038/nm.3913.

85.

Zhu J, Cynader MS, Jia W. TDP-43 inhibits NF-κB activity by blocking p65 nuclear translocation. Scavone C, ed. PLoS One. 2015;10(11):e0142296. https://doi.org/10.1371/journal.pone.0142296.CrossRefPubMedPubMedCentral

86.

Gulino R, Forte S, Parenti R, Gulisano M. TDP-43 as a modulator of synaptic plasticity in a mouse model of spinal motoneuron degeneration. CNS Neurol Disord Drug Targets. 2015;14(1):55–60. https://doi.org/10.2174/1871527314666150116115414.CrossRefPubMed

87.

Chen HJ, Mitchell JC, Novoselov S, et al. The heat shock response plays an important role in TDP-43 clearance: evidence for dysfunction in amyotrophic lateral sclerosis. Brain. 2016;139(5):1417–32. https://doi.org/10.1093/brain/aww028.CrossRefPubMedPubMedCentral

88.

Jinwal UK, Abisambra JF, Zhang J, et al. Cdc37/Hsp90 protein complex disruption triggers an autophagic clearance cascade for TDP-43 protein. J Biol Chem. 2012;287(29):24814–20. https://doi.org/10.1074/jbc.M112.367268.CrossRefPubMedPubMedCentral

89.

Donnenfeld H, Kascsak RJ, Bartfeld H. Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients. J Neuroimmunol. 1984;6(1):51–7. https://doi.org/10.1016/0165-5728(84)90042-0.CrossRefPubMed

90.

Engelhardt JI, Siklós L, Kőműves L, Smith RG, Appel SH. Antibodies to calcium channels from ALS patients passively transferred to mice selectively increase intracellular calcium and induce ultrastructural changes in motoneurons. Synapse. 1995;20(3):185–99. https://doi.org/10.1002/syn.890200302.CrossRefPubMed

91.

Janelidze S, Hertze J, Nägga K, et al. Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol Aging. 2017;51:104–12. https://doi.org/10.1016/j.neurobiolaging.2016.11.017.CrossRefPubMedPubMedCentral

92.

Bowman GL, Kaye JA, Moore M, Waichunas D, Carlson NE, Quinn JF. Blood-brain barrier impairment in Alzheimer disease: Stability and functional significance. Neurology. 2007;68(21):1809–14. https://doi.org/10.1212/01.wnl.0000262031.18018.1a.CrossRefPubMed

Title: TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model
Authors: Frank Zamudio
Anjanet R. Loon
Shayna Smeltzer
Khawla Benyamine
Nanda K. Navalpur Shanmugam
Nicholas J. F. Stewart
Daniel C. Lee
Kevin Nash
Maj-Linda B. Selenica
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Frontotemporal Dementia
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01952-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

Disease propagation in amyotrophic lateral sclerosis (ALS): an interplay between genetics and environment

G-protein-coupled estrogen receptor activation upregulates interleukin-1 receptor antagonist in the hippocampus after global cerebral ischemia: implications for neuronal self-defense

CX3CR1-microglia mediates neuroinflammation and blood pressure regulation in the nucleus tractus solitarii of fructose-induced hypertensive rats

Short-term resistance exercise inhibits neuroinflammation and attenuates neuropathological changes in 3xTg Alzheimer’s disease mice

The immune system on the TRAIL of Alzheimer’s disease

Perturbation of gut microbiota decreases susceptibility but does not modulate ongoing autoimmune neurological disease