CoChat
Sign Up
Cited by 324Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

Open access
Xie, Junhua, Van Hoecke, Lien, Vandenbroucke, Roosmarijn E.·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2021.796867PMC PMC8770958
Open this paper in CoChat — free accountOpen PDF

Abstract

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which the therapeutic effect is not yet conclusively proven, only symptomatic medication that is effective for some AD patients is available. In order to be able to design more rational and effective treatments, our understanding of the mechanisms behind the pathogenesis and progression of AD urgently needs to be improved. Over the last years, it became increasingly clear that peripheral inflammation is one of the detrimental factors that can contribute to the disease. Here, we discuss the current understanding of how systemic and intestinal (referred to as the gut-brain axis) inflammatory processes may affect brain pathology, with a specific focus on AD. Moreover, we give a comprehensive overview of the different preclinical as well as clinical studies that link peripheral Inflammation to AD initiation and progression. Altogether, this review broadens our understanding of the mechanisms behind AD pathology and may help in the rational design of further research aiming to identify novel therapeutic targets.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fimmu.2021.796867

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Systemic inflammation from peripheral immune system, such as caused by infection or gut microbiota perturbation, occurring decades before typical dementia onset, may promote progression of neurodegenerative processes.

    “Together, these findings suggest that systemic inflammation from the peripheral immune system, such as that caused by infection or gut microbiota perturbation, occurring decades before the typical age of dementia onset, may promote the progression of neurodegenerative processes.94”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [94]

    The Conclusion (page unavailable) says systemic inflammation might drive the initiation and progression of Alzheimer’s disease, while the clinical-studies and gut-inflammation sections discuss infection and altered gut microbiota as contributors. The paper does not establish the claim’s specific timing—that such inflammation occurs decades before the typical age of dementia onset. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Peripheral inflammatory molecules induced by acute systemic viral or bacterial infections can affect brain function through neural and humoral pathways.

    “Multiple clinical and experimental studies have demonstrated that peripheral inflammatory molecules induced by acute systemic viral or bacterial infections can affect brain function through neural and humoral pathways.94,98,99”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [94]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 168

  1. [1]Wong W. Economic Burden of Alzheimer Disease and Managed Care Considerations. Am J Manag Care (2020) 26: S177–83. doi: 10.37765/ajmc.2020.88482 32840331 · DOI
  2. [2]Masters CL Bateman R Blennow K Rowe CC Sperling RA Cummings JL. Alzheimer’s Disease. Nat Rev Dis Primers (2015) 1: 15056. doi: 10.1038/nrdp.2015.56 27188934 · DOI · Paper page
  3. [3]Rabinovici GD. Controversy and Progress in Alzheimer’s Disease — FDA Approval of Aducanumab. N Engl J Med (2021) 385: 771–4. doi: 10.1056/NEJMp2111320 34320284 · DOI · Paper page
  4. [5]Arvanitakis Z Grodstein F Bienias JL Schneider JA Wilson RS Kelly JF. Relation of NSAIDs to Incident AD, Change in Cognitive Function, and AD Pathology. Neurology (2008) 70: 2219–25. doi: 10.1212/01.wnl.0000313813.48505.86 18519870 · DOI
  5. [6]Breitner JC Haneuse SJ Walker R Dublin S Crane PK Gray SL. Risk of Dementia and AD With Prior Exposure to NSAIDs in an Elderly Community-Based Cohort. Neurology (2009) 72: 1899–905. doi: 10.1212/WNL.0b013e3181a18691 PMC2690966 19386997 · DOI
  6. [7]Doody RS Raman R Farlow M Iwatsubo T Vellas B Joffe S. A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease. N Engl J Med (2013) 369: 341–50. doi: 10.1056/NEJMoa1210951 23883379 · DOI · Paper page
  7. [10]Orgogozo JM Gilman S Dartigues JF Laurent B Puel M Kirby LC. Subacute Meningoencephalitis in a Subset of Patients With AD After Abeta42 Immunization. Neurology (2003) 61: 46– 54. doi: 10.1212/01.wnl.0000073623.84147.a8 12847155 · DOI · Paper page
  8. [11]Heneka MT Golenbock DT Latz E. Innate Immunity in Alzheimer’s Disease. Nat Immunol (2015) 16: 229–36. doi: 10.1038/ni.3102 25689443 · DOI · Paper page
  9. [12]Frost GR Jonas LA Li YM. Friend, Foe or Both? Immune Activity in Alzheimer’s Disease. Front Aging Neurosci (2019) 11: 337. doi: 10.3389/fnagi.2019.00337 31920620 PMC6916654 · DOI
  10. [13]Labzin LI Heneka MT Latz E. Innate Immunity and Neurodegeneration. Annu Rev Med (2018) 69: 437–49. doi: 10.1146/annurev-med-050715-104343 29106805 · DOI · Paper page
  11. [14]Kamboh MI Demirci FY Wang X Minster RL Carrasquillo MM Pankratz VS. Genome-Wide Association Study of Alzheimer’s Disease. Transl Psychiatry (2012) 2: e117. doi: 10.1038/tp.2012.45 22832961 PMC3365264 · DOI
  12. [16]Holmes C. Review: Systemic Inflammation and Alzheimer’s Disease. Neuropathol Appl Neurobiol (2013) 39: 51– 68. doi: 10.1111/j.1365-2990.2012.01307.x 23046210 · DOI · Paper page
  13. [18]Perry VH. Contribution of Systemic Inflammation to Chronic Neurodegeneration. Acta Neuropathol (2010) 120: 277–86. doi: 10.1007/s00401-010-0722-x 20644946 · DOI
  14. [19]Pavlov VA Tracey KJ. The Cholinergic Anti-Inflammatory Pathway. Brain Behav Immun (2005) 19: 493–9. doi: 10.1016/j.bbi.2005.03.015 15922555 · DOI · Paper page
  15. [20]Zielinski MR Dunbrasky DL Taishi P Souza G Krueger JM. Vagotomy Attenuates Brain Cytokines and Sleep Induced by Peripherally Administered Tumor Necrosis Factor-Alpha and Lipopolysaccharide in Mice. Sleep (2013) 36: 1227–38. doi: 10.5665/sleep.2892 PMC3700720 23904683 · DOI · Paper page
  16. [21]Paouri E Gcorgopoulos S. Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer’s Disease. Curr Alzheimer Res (2019) 16: 559–74. doi: 10.2174/1567205016666190321154618 30907316 · DOI
  17. [22]Kempuraj D Thangavel R Selvakumar GP Zaheer S Ahmed ME Raikwar SP. Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration. Front Cell Neurosci (2017) 11: 216. doi: 10.3389/fncel.2017.00216 28790893 PMC5522882 · DOI
  18. [26]Bellettato CM Scarpa M. Possible Strategies to Cross the Blood-Brain Barrier. Ital J Pediatr (2018) 44: 131. doi: 10.1186/s13052-018-0563-0 30442184 PMC6238258 · DOI
  19. [27]Jiao Z Zhang W Chen C Zhu X Chen X Zhou M. Gene Dysfunction Mediates Immune Response to Dopaminergic Degeneration in Parkinson’s Disease. ACS Chem Neurosci (2019) 10: 803–11. doi: 10.1021/acschemneuro.8b00373 30289236 · DOI
  20. [28]Ghersi-Egea JF Strazielle N Catala M Silva-Vargas V Doetsch F Engelhardt B. Molecular Anatomy and Functions of the Choroidal Blood-Cerebrospinal Fluid Barrier in Health and Disease. Acta Neuropathol (2018) 135: 337–61. doi: 10.1007/s00401-018-1807-1 29368213 · DOI · Paper page
  21. [29]Gorle N Blaecher C Bauwens E Vandendriessche C Balusu S Vandewalle J. The Choroid Plexus Epithelium as a Novel Player in the Stomach-Brain Axis During Helicobacter Infection. Brain Behav Immun (2018) 69: 35– 47. doi: 10.1016/j.bbi.2017.12.010 29258921 · DOI · Paper page
  22. [30]Kooij G Kopplin K Blasig R Stuiver M Koning N Goverse G. Disturbed Function of the Blood-Cerebrospinal Fluid Barrier Aggravates Neuro-Inflammation. Acta Neuropathol (2014) 128: 267–77. doi: 10.1007/s00401-013-1227-1 24356983 · DOI
  23. [31]Marques F Sousa JC Coppola G Geschwind DH Sousa N Palha JA. The Choroid Plexus Response to a Repeated Peripheral Inflammatory Stimulus. BMC Neurosci (2009) 10: 135. doi: 10.1186/1471-2202-10-135 19922669 PMC2784788 · DOI
  24. [32]Balusu S Van Wonterghem E De Rycke R Raemdonck K Stremersch S Gevaert K. Identification of a Novel Mechanism of Blood-Brain Communication During Peripheral Inflammation via Choroid Plexus-Derived Extracellular Vesicles. EMBO Mol Med (2016) 8: 1162–83. doi: 10.15252/emmm.201606271 PMC5048366 27596437 · DOI
  25. [33]Matsumura K Kobayashi S. Signaling the Brain in Inflammation: The Role of Endothelial Cells. Front Biosci (2004) 9: 2819–26. doi: 10.2741/1439 15353317 · DOI
  26. [35]Cunningham C Wilcockson DC Campion S Lunnon K Perry VH. Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death During Chronic Neurodegeneration. J Neurosci (2005) 25: 9275–84. doi: 10.1523/Jneurosci.2614-05.2005 PMC6725757 16207887 · DOI · Paper page
  27. [37]Wang LM Wu Q Kirk RA Horn KP Ebada Salem AH Hoffman JM. Lipopolysaccharide Endotoxemia Induces Amyloid-Beta and P-Tau Formation in the Rat Brain. Am J Nucl Med Mol Imaging (2018) 8: 86– 99. 29755842 PMC5944824
  28. [39]Lee JW Lee YK Yuk DY Choi DY Ban SB Oh KW. Neuro-Inflammation Induced by Lipopolysaccharide Causes Cognitive Impairment Through Enhancement of Beta-Amyloid Generation. J Neuroinflamm (2008) 5: 37. doi: 10.1186/1742-2094-5-37 PMC2556656 18759972 · DOI · Paper page
  29. [40]Tejera D Mercan D Sanchez-Caro JM Hanan M Greenberg D Soreq H. Systemic Inflammation Impairs Microglial A Beta Clearance Through NLRP3 Inflammasome. EMBO J (2019) 38: e101064. doi: 10.15252/embj.2018101064 31359456 PMC6717897 · DOI · Paper page
  30. [41]Wang F Zhang ZZ Cao L Yang QG Lu QF Chen GH. Lipopolysaccharide Exposure During Late Embryogenesis Triggers and Drives Alzheimer-Like Behavioral and Neuropathological Changes in CD-1 Mice. Brain Behav (2020) 10: e01546. doi: 10.1002/brb3.1546 31997558 PMC7066339 · DOI
  31. [43]Sly LM Krzesicki RF Brashler JR Buhl AE McKinley DD Carter DB. Endogenous Brain Cytokine mRNA and Inflammatory Responses to Lipopolysaccharide Are Elevated in the Tg2576 Transgenic Mouse Model of Alzheimer’s Disease. Brain Res Bull (2001) 56: 581–8. doi: 10.1016/S0361-9230(01)00730-4 11786245 · DOI
  32. [46]Michaud JP Halle M Lampron A Theriault P Prefontaine P Filali M. Toll-Like Receptor 4 Stimulation With the Detoxified Ligand Monophosphoryl Lipid A Improves Alzheimer’s Disease-Related Pathology. Proc Natl Acad Sci USA (2013) 110: 1941–6. doi: 10.1073/pnas.1215165110 PMC3562771 23322736 · DOI
  33. [47]Xie J Gorlé N Vandendriessche C Van Imschoot G Van Wonterghem E Van Cauwenberghe C. Low-Grade Peripheral Inflammation Affects Brain Pathology in the AppNL-G-F Mouse Model of Alzheimer’s Disease. Acta Neuropathol Commun (2021) 9: 163. doi: 10.1186/s40478-021-01253-z 34620254 PMC8499584 · DOI
  34. [49]Hennessy E Gormley S Lopez-Rodriguez AB Murray C Murray C Cunningham C. Systemic TNF-alpha Produces Acute Cognitive Dysfunction and Exaggerated Sickness Behavior When Superimposed Upon Progressive Neurodegeneration. Brain Behav Immun (2017) 59: 233–44. doi: 10.1016/j.bbi.2016.09.011 PMC5176008 27633985 · DOI
  35. [50]Go M Kou JH Lim JE Yang JL Fukuchi KI. Microglial Response to LPS Increases in Wild-Type Mice During Aging But Diminishes in an Alzheimer’s Mouse Model: Implication of TLR4 Signaling in Disease Progression. Biochem Biophys Res Commun (2016) 479: 331–7. doi: 10.1016/j.bbrc.2016.09.073 PMC5048480 27641666 · DOI
  36. [51]Thygesen C Ilkjaer L Kempf SJ Hemdrup AL Von Linstowl CU Babcock AA. Diverse Protein Profiles in CNS Myeloid Cells and CNS Tissue From Lipopolysaccharide- and Vehicle-Injected APP(SWE)/PS1(Delta E9) Transgenic Mice Implicate Cathepsin Z in Alzheimer’s Disease. Front Cell Neurosci (2018) 12: 397. doi: 10.3389/fncel.2018.00397 30459560 PMC6232379 · DOI
  37. [52]Malm TM Koistinaho M Parepalo M Vatanen T Ooka A Karlsson S. Bone-Marrow-Derived Cells Contribute to the Recruitment of Microglial Cells in Response to Beta-Amyloid Deposition in APP/PS1 Double Transgenic Alzheimer Mice. Neurobiol Dis (2005) 18: 134–42. doi: 10.1016/j.nbd.2004.09.009 15649704 · DOI · Paper page
  38. [54]Beyer MMS Lonnemann N Remus A Latz E Heneka MT Korte M. Enduring Changes in Neuronal Function Upon Systemic Inflammation Are NLRP3 Inflammasome Dependent. J Neurosci (2020) 40: 5480–94. doi: 10.1523/JNEUROSCI.0200-20.2020 PMC7343321 32499379 · DOI · Paper page
  39. [56]Agostini A Ding YC Bai L Kendall DA Pardon MC. Sex-Specific Hippocampal Metabolic Signatures at the Onset of Systemic Inflammation With Lipopolysaccharide in the APPswe/PS1dE9 Mouse Model of Alzheimer’s Disease. Brain Behav Immun (2020) 83: 87– 111. doi: 10.1016/j.bbi.2019.09.019 31560941 PMC6928588 · DOI
  40. [59]McAlpine FE Lee JK Harms AS Ruhn KA Blurton-Jones M Hong J. Inhibition of Soluble TNF Signaling in a Mouse Model of Alzheimer’s Disease Prevents Pre-Plaque Amyloid-Associated Neuropathology. Neurobiol Dis (2009) 34: 163–77. doi: 10.1016/j.nbd.2009.01.006 PMC2948857 19320056 · DOI
  41. [60]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: 8843–53. doi: 10.1523/JNEUROSCI.2868-05.2005 PMC6725603 16192374 · DOI · Paper page
  42. [61]Valero J Mastrella G Neiva I Sanchez S Malva JO. Long-Term Effects of an Acute and Systemic Administration of LPS on Adult Neurogenesis and Spatial Memory. Front Neurosci (2014) 8: 83. doi: 10.3389/fnins.2014.00083 24795557 PMC4001049 · DOI
  43. [62]Joshi YB Giannopoulos PF Chu J Pratico D. Modulation of Lipopolysaccharide-Induced Memory Insult, Gamma-Secretase, and Neuroinflammation in Triple Transgenic Mice by 5-Lipoxygenase. Neurobiol Aging (2014) 35: 1024–31. doi: 10.1016/j.neurobiolaging.2013.11.016 PMC3948206 24332986 · DOI
  44. [63]Montacute R Foley K Forman R Else KJ Cruickshank SM Allan SM. Enhanced Susceptibility of Triple Transgenic Alzheimer’s Disease (3xtg-AD) Mice to Acute Infection. J Neuroinflamm (2017) 14: 50. doi: 10.1186/s12974-017-0826-5 PMC5346250 28284226 · DOI · Paper page
  45. [64]Herber DL Mercer M Roth LM Symmonds K Maloney J Wilson N. Microglial Activation Is Required for A Beta Clearance After Intracranial Injection of Lipopolysaccharide in APP Transgenic Mice. J Neuroimmune Pharmacol (2007) 2: 222–31. doi: 10.1007/s11481-007-9069-z 18040847 · DOI
  46. [65]Herber DL Roth LM Wilson D Wilson N Mason JE Morgan D. Time-Dependent Reduction in A Beta Levels After Intracranial LPS Administration in APP Transgenic Mice. Exp Neurol (2004) 190: 245–53. doi: 10.1016/j.expneurol.2004.07.007 15473997 · DOI
  47. [67]Barton SM Janve VA McClure R Anderson A Matsubara JA Gore JC. Lipopolysaccharide Induced Opening of the Blood Brain Barrier on Aging 5XFAD Mouse Model. J Alzheimers Dis (2019) 67: 503–13. doi: 10.3233/Jad-180755 PMC9026569 30584141 · DOI
  48. [68]Hayashi K Hasegawa Y Takemoto Y Gao C Takeya H Komohara Y. Continuous Intracerebroventricular Injection of Porphyromonas Gingivalis Lipopolysaccharide Induces Systemic Organ Dysfunction in a Mouse Model of Alzheimer’s Disease. Exp Gerontol (2019) 120: 1– 5. doi: 10.1016/j.exger.2019.02.007 30786259 · DOI
  49. [69]Kantarci A Tognoni CM Yaghmoor W Marghalani A Stephens D Ahn JY. Microglial Response to Experimental Periodontitis in a Murine Model of Alzheimer’s Disease. Sci Rep (2020) 10: 18561. doi: 10.1038/s41598-020-75517-4 33122702 PMC7596239 · DOI
  50. [70]Combrinck MI Perry VH Cunningham C. Peripheral Infection Evokes Exaggerated Sickness Behaviour in Pre-Clinical Murine Prion Disease. Neuroscience (2002) 112: 7– 11. doi: 10.1016/s0306-4522(02)00030-1 12044467 · DOI · Paper page
  51. [71]Cunningham C Campion S Lunnon K Murray CL Woods JF Deacon RM. Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease. Biol Psychiatry (2009) 65: 304–12. doi: 10.1016/j.biopsych.2008.07.024 PMC2633437 18801476 · DOI · Paper page
  52. [72]Field R Campion S Warren C Murray C Cunningham C. Systemic Challenge With the TLR3 Agonist Poly I:C Induces Amplified IFN Alpha/Beta and IL-1 Beta Responses in the Diseased Brain and Exacerbates Chronic Neurodegeneration. Brain Behav Immun (2010) 24: 996– 1007. doi: 10.1016/j.bbi.2010.04.004 20399848 PMC3334265 · DOI
  53. [73]Ishida N Ishihara Y Ishida K Tada H Funaki-Kato Y Hagiwara M. Periodontitis Induced by Bacterial Infection Exacerbates Features of Alzheimer’s Disease in Transgenic Mice. NPJ Aging Mech Dis (2017) 3: 15. doi: 10.1038/s41514-017-0015-x 29134111 PMC5673943 · DOI
  54. [74]Ray S Britschgi M Herbert C Takeda-Uchimura Y Boxer A Blennow K. Classification and Prediction of Clinical Alzheimer’s Diagnosis Based on Plasma Signaling Proteins. Nat Med (2007) 13: 1359–62. doi: 10.1038/nm1653 17934472 · DOI · Paper page
  55. [75]Chouhan JK Fowler SB Webster CI Teeling JL. The ME7 Prion Model of Neurodegeneration as a Tool to Understand and Target Neuroinflammation in Alzheimer’s Disease. Drug Discov Today Dis Models (2017) 25-26: 45– 52. doi: 10.1016/j.ddmod.2018.10.004 · DOI
  56. [76]Nie R Wu Z Ni J Zeng F Yu W Zhang Y. Porphyromonas Gingivalis Infection Induces Amyloid-Beta Accumulation in Monocytes/Macrophages. J Alzheimers Dis (2019) 72: 479–94. doi: 10.3233/JAD-190298 31594220 · DOI
  57. [77]Wang XL Zeng J Feng J Tian YT Liu YJ Qiu M. Helicobacter Pylori Filtrate Impairs Spatial Learning and Memory in Rats and Increases Beta-Amyloid by Enhancing Expression of Presenilin-2. Front Aging Neurosci (2014) 6: 66. doi: 10.3389/fnagi.2014.00066 24782763 PMC3990046 · DOI
  58. [78]Wang XL Zeng J Yang Y Xiong Y Zhang ZH Qiua M. Helicobacter Pylori Filtrate Induces Alzheimer-Like Tau Hyperphosphorylation by Activating Glycogen Synthase Kinase-3 Beta. J Alzheimers Dis (2015) 43: 153–65. doi: 10.3233/Jad-140198 25079798 · DOI
  59. [79]Laur AM Floch P Chambonnier L Benejat L Korolik V Giese A. Regulatory T Cells May Participate in Helicobacter Pylori Persistence in Gastric MALT Lymphoma: Lessons From an Animal Model. Oncotarget (2016) 7: 3384–92. doi: 10.18632/oncotarget.6492 PMC4823114 26657504 · DOI
  60. [80]Albaret G Sifre E Floch P Laye S Aubert A Dubus P. Alzheimer’s Disease and Helicobacter Pylori Infection: Inflammation From Stomach to Brain? J Alzheimers Dis (2020) 73: 801–9. doi: 10.3233/Jad-190496 31868664 · DOI
  61. [81]Roubaud Baudron C Chambonnier L Buissionnière A Giese A Macrez N Cho Y. An Eighteen-Month Helicobacter Infection Does Not Induce Amyloid Plaques or Neuroinflammation in Brains of Wild Type C57BL/6J Mice. J Alzheimers Dis (2015) 45: 1045–50. doi: 10.3233/JAD-143129 25697698 · DOI
  62. [82]Allison CC Ferrero RL. Role of Virulence Factors and Host Cell Signaling in the Recognition of Helicobacter Pylori and the Generation of Immune Responses. Future Microbiol (2010) 5: 1233–55. doi: 10.2217/fmb.10.84 20722601 · DOI
  63. [83]Cairns DM Rouleau N Parker RN Walsh KG Gehrke L Kaplan DL. A 3D Human Brain-Like Tissue Model of Herpes-Induced Alzheimer’s Disease. Sci Adv (2020) 6: eaay8828. doi: 10.1126/sciadv.aay8828 32494701 PMC7202879 · DOI · Paper page
  64. [84]Ngo HM Zhou Y Lorenzi H Wang K Kim TK Zhou Y. Toxoplasma Modulates Signature Pathways of Human Epilepsy, Neurodegeneration & Cancer. Sci Rep (2017) 7: 11496. doi: 10.1038/s41598-017-10675-6 28904337 PMC5597608 · DOI
  65. [86]Pisa D Alonso R Juarranz A Rabano A Carrasco L. Direct Visualization of Fungal Infection in Brains From Patients With Alzheimer’s Disease. J Alzheimers Dis (2015) 43: 613–24. doi: 10.3233/Jad-141386 25125470 · DOI
  66. [87]Civitelli L Marcocci ME Celestino I Piacentini R Garaci E Grassi C. Herpes Simplex Virus Type 1 Infection in Neurons Leads to Production and Nuclear Localization of APP Intracellular Domain (AICD): Implications for Alzheimer’s Disease Pathogenesis. J Neurovirol (2015) 21: 480–90. doi: 10.1007/s13365-015-0344-0 25925093 · DOI
  67. [89]Xia X Wang Y Zheng J. COVID-19 and Alzheimer’s Disease: How One Crisis Worsens the Other. Transl Neurodegener (2021) 10: 15. doi: 10.1186/s40035-021-00237-2 33941272 PMC8090526 · DOI
  68. [90]Jiao L Yang Y Yu W Zhao Y Long H Gao J. The Olfactory Route Is a Potential Way for SARS-CoV-2 to Invade the Central Nervous System of Rhesus Monkeys. Signal Transduct Target Ther (2021) 6: 169. doi: 10.1038/s41392-021-00591-7 33895780 PMC8065334 · DOI
  69. [91]Margraf A Ludwig N Zarbock A Rossaint J. Systemic Inflammatory Response Syndrome After Surgery: Mechanisms and Protection. Anesth Analg (2020) 131: 1693–707. doi: 10.1213/ANE.0000000000005175 33186158 · DOI
  70. [92]Gasparotto J Girardi CS Somensi N Ribeiro CT Moreira JCF Michels M. Receptor for Advanced Glycation End Products Mediates Sepsis-Triggered Amyloid-Beta Accumulation, Tau Phosphorylation, and Cognitive Impairment. J Biol Chem (2018) 293: 226–44. doi: 10.1074/jbc.M117.786756 PMC5766916 29127203 · DOI · Paper page
  71. [93]Huang C Irwin MG Wong GTC Chang RCC. Evidence of the Impact of Systemic Inflammation on Neuroinflammation From a Non-Bacterial Endotoxin Animal Model. J Neuroinflamm (2018) 15: 147. doi: 10.1186/s12974-018-1163-z PMC5960121 29776428 · DOI
  72. [94]Fidalgo AR Cibelli M White JPM Nagy I Maze M Ma DQ. Systemic Inflammation Enhances Surgery-Induced Cognitive Dysfunction in Mice. Neurosci Lett (2011) 498: 63–6. doi: 10.1016/j.neulet.2011.04.063 21575676 · DOI
  73. [95]Li L Cao D Garber DW Kim H Fukuchi K. Association of Aortic Atherosclerosis With Cerebral Beta-Amyloidosis and Learning Deficits in a Mouse Model of Alzheimer’s Disease. Am J Pathol (2003) 163: 2155–64. doi: 10.1016/s0002-9440(10)63572-9 PMC1892402 14633589 · DOI
  74. [96]Franciosi S Gama Sosa MA English DF Oler E Oung T Janssen WG. Novel Cerebrovascular Pathology in Mice Fed a High Cholesterol Diet. Mol Neurodegener (2009) 4: 42. doi: 10.1186/1750-1326-4-42 19852847 PMC2774302 · DOI
  75. [97]Kimura N. Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological Evidence From Animal Models. Int J Mol Sci (2016) 17: 503. doi: 10.3390/ijms17040503 27058526 PMC4848959 · DOI
  76. [98]Tucsek Z Toth P Sosnowska D Gautam T Mitschelen M Koller A. Obesity in Aging Exacerbates Blood-Brain Barrier Disruption, Neuroinflammation, and Oxidative Stress in the Mouse Hippocampus: Effects on Expression of Genes Involved in Beta-Amyloid Generation and Alzheimer’s Disease. J Gerontol A Biol Sci Med Sci (2014) 69: 1212–26. doi: 10.1093/gerona/glt177 PMC4172034 24269929 · DOI
  77. [99]Theriault P ElAli A Rivest S. High Fat Diet Exacerbates Alzheimer’s Disease-Related Pathology in APPswe/PS1 Mice. Oncotarget (2016) 7: 67808–27. doi: 10.18632/oncotarget.12179 PMC5356521 27661129 · DOI
  78. [103]Motta M Imbesi R Di Rosa M Stivala F Malaguarnera L. Altered Plasma Cytokine Levels in Alzheimer’s Disease: Correlation With the Disease Progression. Immunol Lett (2007) 114: 46– 51. doi: 10.1016/j.imlet.2007.09.002 17949824 · DOI
  79. [104]Clark IA Atwood CS. Is TNF a Link Between Aging-Related Reproductive Endocrine Dyscrasia and Alzheimer’s Disease? J Alzheimers Dis (2011) 27: 691–9. doi: 10.3233/Jad-2011-110887 PMC3753178 21891866 · DOI
  80. [105]Butchart J Birch B Bassily R Wolfe L Holmes C. Male Sex Hormones and Systemic Inflammation in Alzheimer Disease. Alzheimer Dis Assoc Disord (2013) 27: 153–6. doi: 10.1097/WAD.0b013e318258cd63 22596080 · DOI
  81. [106]Surendranathan A Su L Mak E Passamonti L Hong YT Arnold R. Early Microglial Activation and Peripheral Inflammation in Dementia With Lewy Bodies. Brain (2018) 141: 3415–27. doi: 10.1093/brain/awy265 PMC6262214 30403785 · DOI · Paper page
  82. [107]Okello A Edison P Archer HA Turkheimer FE Kennedy J Bullock R. Microglial Activation and Amyloid Deposition in Mild Cognitive Impairment A PET Study. Neurology (2009) 72: 56– 62. doi: 10.1212/01.wnl.0000338622.27876.0d 19122031 PMC2817573 · DOI · Paper page
  83. [108]Savva GM Wharton SB Ince PG Forster G Matthews FE Brayne C. Age, Neuropathology, and Dementia. N Engl J Med (2009) 360: 2302–9. doi: 10.1056/NEJMoa0806142 19474427 · DOI · Paper page
  84. [111]Kountouras J Tsolaki M Boziki M Gavalas E Zavos C Stergiopoulos C. Association Between Helicobacter Pylori Infection and Mild Cognitive Impairment. Eur J Neurol (2007) 14: 976–82. doi: 10.1111/j.1468-1331.2007.01827.x 17718688 · DOI
  85. [112]Kountouras J Tsolaki M Gavalas E Boziki M Zavos C Karatzoglou P. Relationship Between Helicobacter Pylori Infection and Alzheimer Disease. Neurology (2006) 66: 938–40. doi: 10.1212/01.wnl.0000203644.68059.5f 16567719 · DOI
  86. [113]Dioguardi M Crincoli V Laino L Alovisi M Sovereto D Mastrangelo F. The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer’s Disease: A Systematic Review. J Clin Med (2020) 9: 495. doi: 10.3390/jcm9020495 PMC7074205 32054121 · DOI
  87. [114]Carter CJ France J Crean S Singhrao SK. The Porphyromonas Gingivalis/Host Interactome Shows Enrichment in GWASdb Genes Related to Alzheimer’s Disease, Diabetes and Cardiovascular Diseases. Front Aging Neurosci (2017) 9: 408. doi: 10.3389/fnagi.2017.00408 29311898 PMC5732932 · DOI
  88. [115]Kamer AR Craig RG Pirraglia E Dasanayake AP Norman RG Boylan RJ. TNF-Alpha and Antibodies to Periodontal Bacteria Discriminate Between Alzheimer’s Disease Patients and Normal Subjects. J Neuroimmunol (2009) 216: 92–7. doi: 10.1016/j.jneuroim.2009.08.013 PMC2783848 19767111 · DOI
  89. [116]Farhad SZ Amini S Khalilian A Barekatain M Mafi M Barekatain M. The Effect of Chronic Periodontitis on Serum Levels of Tumor Necrosis Factor-Alpha in Alzheimer Disease. Dent Res J (Isfahan) (2014) 11: 549–52. PMC4241606 25426144
  90. [117]Poole S Singhrao SK Kesavalu L Curtis MA Crean S. Determining the Presence of Periodontopathic Virulence Factors in Short-Term Postmortem Alzheimer’s Disease Brain Tissue. J Alzheimers Dis (2013) 36: 665–77. doi: 10.3233/Jad-121918 23666172 · DOI
  91. [119]Ide M Harris M Stevens A Sussams R Hopkins V Culliford D. Periodontitis and Cognitive Decline in Alzheimer’s Disease. PloS One (2016) 11: e0151081. doi: 10.1371/journal.pone.0151081 26963387 PMC4786266 · DOI · Paper page
  92. [120]Montoya JAG Barrios R Sanchez-Lara I Ramos P Carnero C Fornieles F. Systemic Inflammatory Impact of Periodontitis on Cognitive Impairment. Gerodontology (2019) 37: 11–8. doi: 10.1111/ger.12431 31347730 · DOI
  93. [121]Wu B Fillenbaum GG Plassman BL Guo L. Association Between Oral Health and Cognitive Status: A Systematic Review. J Am Geriatr Soc (2016) 64: 739–51. doi: 10.1111/jgs.14036 PMC4986993 27037761 · DOI
  94. [122]Doulberis M Kotronis G Thomann R Polyzos SA Boziki M Gialamprinou D. Review: Impact of Helicobacter Pylori on Alzheimer’s Disease: What Do We Know So Far? Helicobacter (2018) 23: e12454. doi: 10.1111/hel.12454 29181894 · DOI
  95. [123]Kountouras J Boziki M Gavalas E Zavos C Deretzi G Grigoriadis N. Increased Cerebrospinal Fluid Helicobacter Pylori Antibody in Alzheimer’s Disease. Int J Neurosci (2009) 119: 765–77. doi: 10.1080/00207450902782083 19326283 · DOI
  96. [124]Roubaud-Baudron C Krolak-Salmon P Quadrio I Megraud F Salles N. Impact of Chronic Helicobacter Pylori Infection on Alzheimer’s Disease: Preliminary Results. Neurobiol Aging (2012) 33: 1009.e11–9. doi: 10.1016/j.neurobiolaging.2011.10.021 22133280 · DOI
  97. [125]Kountouras J Boziki M Gavalas E Zavos C Deretzi G Chatzigeorgiou S. Five-Year Survival After Helicobacter Pylori Eradication in Alzheimer Disease Patients. Cognit Behav Neurol (2010) 23: 199– 204. doi: 10.1097/WNN.0b013e3181df3034 20829670 · DOI
  98. [126]Kountouras J Boziki M Gavalas E Zavos C Grigoriadis N Deretzi G. Eradication of Helicobacter Pylori May Be Beneficial in the Management of Alzheimer’s Disease. J Neurol (2009) 256: 758–67. doi: 10.1007/s00415-009-5011-z 19240960 · DOI
  99. [127]Shiota S Murakami K Yoshiiwa A Yamamoto K Ohno S Kuroda A. The Relationship Between Helicobacter Pylori Infection and Alzheimer’s Disease in Japan. J Neurol (2011) 258: 1460–3. doi: 10.1007/s00415-011-5957-5 PMC3742106 21336779 · DOI
  100. [128]Graham DY Miftahussurur M. Helicobacter Pylori Urease for Diagnosis of Helicobacter Pylori Infection: A Mini Review. J Adv Res (2018) 13: 51–7. doi: 10.1016/j.jare.2018.01.006 PMC6077137 30094082 · DOI
  101. [129]Wozniak MA Mee AP Itzhaki RF. Herpes Simplex Virus Type 1 DNA Is Located Within Alzheimer’s Disease Amyloid Plaques. J Pathol (2009) 217: 131–8. doi: 10.1002/path.2449 18973185 · DOI · Paper page
  102. [130]Tsai MC Cheng WL Sheu JJ Huang CC Shia BC Kao LT. Increased Risk of Dementia Following Herpes Zoster Ophthalmicus. PloS One (2017) 12: e0188490. doi: 10.1371/journal.pone.0188490 29166672 PMC5699837 · DOI · Paper page
  103. [133]Kwok MK Schooling CM. Herpes Simplex Virus and Alzheimer’s Disease: A Mendelian Randomization Study. Neurobiol Aging (2021) 99: 101.e11–3. doi: 10.1016/j.neurobiolaging.2020.09.025 33139072 · DOI · Paper page
  104. [134]Warren-Gash C Forbes HJ Williamson E Breuer J Hayward AC Mavrodaris A. Human Herpesvirus Infections and Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. Sci Rep (2019) 9: 4743. doi: 10.1038/s41598-019-41218-w 30894595 PMC6426940 · DOI · Paper page
  105. [135]McArdle MA Finucane OM Connaughton RM McMorrow AM Roche HM. Mechanisms of Obesity-Induced Inflammation and Insulin Resistance: Insights Into the Emerging Role of Nutritional Strategies. Front Endocrinol (Lausanne) (2013) 4: 52. doi: 10.3389/fendo.2013.00052 23675368 PMC3650620 · DOI
  106. [136]Spauwen PJ Kohler S Verhey FR Stehouwer CD van Boxtel MP. Effects of Type 2 Diabetes on 12-Year Cognitive Change: Results From the Maastricht Aging Study. Diabetes Care (2013) 36: 1554–61. doi: 10.2337/dc12-0746 PMC3661848 23275366 · DOI
  107. [137]Ding J Strachan MW Reynolds RM Frier BM Deary IJ Fowkes FG. Diabetic Retinopathy and Cognitive Decline in Older People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study. Diabetes (2010) 59: 2883–9. doi: 10.2337/db10-0752 PMC2963547 20798334 · DOI
  108. [138]Hassing LB Dahl AK Pedersen NL Johansson B. Overweight in Midlife Is Related to Lower Cognitive Function 30 Years Later: A Prospective Study With Longitudinal Assessments. Dement Geriatr Cognit Disord (2010) 29: 543–52. doi: 10.1159/000314874 PMC3202952 20606436 · DOI
  109. [139]Qizilbash N Gregson J Johnson ME Pearce N Douglas I Wing K. BMI and Risk of Dementia in Two Million People Over Two Decades: A Retrospective Cohort Study. Lancet Diabetes Endocrinol (2015) 3: 431–6. doi: 10.1016/S2213-8587(15)00033-9 25866264 · DOI
  110. [140]Crane PK Walker R Hubbard RA Li G Nathan DM Zheng H. Glucose Levels and Risk of Dementia. N Engl J Med (2013) 369: 540–8. doi: 10.1056/NEJMoa1215740 PMC3955123 23924004 · DOI · Paper page
  111. [143]McManus RM Higgins SC Mills KHG Lynch MA. Respiratory Infection Promotes T Cell Infiltration and Amyloid-Beta Deposition in APP/PS1 Mice. Neurobiol Aging (2014) 35: 109–21. doi: 10.1016/j.neurobiolaging.2013.07.025 23993702 · DOI
  112. [144]Solito E Sastre M. Microglia Function in Alzheimer’s Disease. Front Pharmacol (2012) 3: 14. doi: 10.3389/fphar.2012.00014 22363284 PMC3277080 · DOI
  113. [149]Siskova Z Tremblay ME. Microglia and Synapse: Interactions in Health and Neurodegeneration. Neural Plast (2013) 2013: 425845. doi: 10.1155/2013/425845 24392228 PMC3874338 · DOI · Paper page
  114. [150]Parkhurst CN Yang G Ninan I Savas JN Yates JR Lafaille JJ. Microglia Promote Learning-Dependent Synapse Formation Through Brain-Derived Neurotrophic Factor. Cell (2013) 155: 1596–609. doi: 10.1016/j.cell.2013.11.030 PMC4033691 24360280 · DOI · Paper page
  115. [151]Brown GC Vilalta A. How Microglia Kill Neurons. Brain Res (2015) 1628: 288–97. doi: 10.1016/j.brainres.2015.08.031 26341532 · DOI
  116. [152]Dean JM Wang X Kaindl AM Gressens P Fleiss B Hagberg H. Microglial MyD88 Signaling Regulates Acute Neuronal Toxicity of LPS-Stimulated Microglia In Vitro. Brain Behav Immun (2010) 24: 776–83. doi: 10.1016/j.bbi.2009.10.018 19903519 · DOI
  117. [155]Nimmervoll B White R Yang JW An SM Henn C Sun JJ. LPS-Induced Microglial Secretion of TNF Alpha Increases Activity-Dependent Neuronal Apoptosis in the Neonatal Cerebral Cortex. Cereb Cortex (2013) 23: 1742–55. doi: 10.1093/cercor/bhs156 22700645 · DOI
  118. [156]Harland M Torres S Liu J Wang X. Neuronal Mitochondria Modulation of LPS-Induced Neuroinflammation. J Neurosci (2020) 40: 1756–65. doi: 10.1523/JNEUROSCI.2324-19.2020 PMC7046320 31937559 · DOI
  119. [157]Heneka MT McManus RM Latz E. Inflammasome Signalling in Brain Function and Neurodegenerative Disease. Nat Rev Neurosci (2018) 19: 610–21. doi: 10.1038/s41583-018-0055-7 30206330 · DOI · Paper page
  120. [159]Youm YH Grant RW McCabe LR Albarado DC Nguyen KY Ravussin A. Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging. Cell Metab (2013) 18: 519–32. doi: 10.1016/j.cmet.2013.09.010 PMC4017327 24093676 · DOI · Paper page
  121. [160]Yun HM Kim JA Hwang CJ Jin P Baek MK Lee JM. Neuroinflammatory and Amyloidogenic Activities of IL-32beta in Alzheimer’s Disease. Mol Neurobiol (2015) 52: 341–52. doi: 10.1007/s12035-014-8860-0 25159479 · DOI
  122. [161]Tarasoff-Conway JM Carare RO Osorio RS Glodzik L Butler T Fieremans E. Clearance Systems in the Brain-Implications for Alzheimer Disease. Nat Rev Neurol (2015) 11: 457–70. doi: 10.1038/nrneurol.2015.119 PMC4694579 26195256 · DOI · Paper page
  123. [163]Keffer J Probert L Cazlaris H Georgopoulos S Kaslaris E Kioussis D. Transgenic Mice Expressing Human Tumour Necrosis Factor: A Predictive Genetic Model of Arthritis. EMBO J (1991) 10: 4025–31. doi: 10.1002/j.1460-2075.1991.tb04978.x PMC453150 1721867 · DOI
  124. [164]Paouri E Tzara O Kartalou GI Zenelak S Georgopoulos S. Peripheral Tumor Necrosis Factor-Alpha (TNF-Alpha) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD/TNF Transgenic Mice. J Neurosci (2017) 37: 5155–71. doi: 10.1523/Jneurosci.2484-16.2017 PMC6596468 28442538 · DOI
  125. [166]Compan V Martin-Sanchez F Baroja-Mazo A Lopez-Castejon G Gomez AI Verkhratsky A. Apoptosis-Associated Speck-Like Protein Containing a CARD Forms Specks But Does Not Activate Caspase-1 in the Absence of NLRP3 During Macrophage Swelling. J Immunol (2015) 194: 1261–73. doi: 10.4049/jimmunol.1301676 PMC4883655 25552542 · DOI
  126. [167]Friker LL Scheiblich H Hochheiser IV Brinkschulte R Riedel D Latz E. Beta-Amyloid Clustering Around ASC Fibrils Boosts Its Toxicity in Microglia. Cell Rep (2020) 30: 3743– 54.e6. doi: 10.1016/j.celrep.2020.02.025 32187546 PMC8729885 · DOI · Paper page
  127. [169]Erickson MA Hansen K Banks WA. Inflammation-Induced Dysfunction of the Low-Density Lipoprotein Receptor-Related Protein-1 at the Blood-Brain Barrier: Protection by the Antioxidant N-Acetylcysteine. Brain Behav Immun (2012) 26: 1085–94. doi: 10.1016/j.bbi.2012.07.003 PMC3434291 22809665 · DOI
  128. [171]Gonzalez-Marrero I Gimenez-Llort L Johanson CE Carmona-Calero EM Castaneyra-Ruiz L Brito-Armas JM. Choroid Plexus Dysfunction Impairs Beta-Amyloid Clearance in a Triple Transgenic Mouse Model of Alzheimer’s Disease. Front Cell Neurosci (2015) 9: 17. doi: 10.3389/fncel.2015.00017 25705176 PMC4319477 · DOI
  129. [172]Redzic Z. Molecular Biology of the Blood-Brain and the Blood-Cerebrospinal Fluid Barriers: Similarities and Differences. Fluids Barriers CNS (2011) 8: 3. doi: 10.1186/2045-8118-8-3 21349151 PMC3045361 · DOI
  130. [173]Van Dyken P Lacoste B. Impact of Metabolic Syndrome on Neuroinflammation and the Blood-Brain Barrier. Front Neurosci (2018) 12: 930. doi: 10.3389/fnins.2018.00930 30618559 PMC6297847 · DOI
  131. [174]Liddelow SA. Development of the Choroid Plexus and Blood-CSF Barrier. Front Neurosci (2015) 9: 32. doi: 10.3389/fnins.2015.00032 25784848 PMC4347429 · DOI
  132. [175]Liu Y Zhang S Li X Liu E Wang X Zhou Q. Peripheral Inflammation Promotes Brain Tau Transmission via Disrupting Blood-Brain Barrier. Biosci Rep (2020) 40: BSR20193629. doi: 10.1042/BSR20193629 32043530 PMC7033313 · DOI
  133. [176]Qin LH Huang W Mo XA Chen YL Wu XH. LPS Induces Occludin Dysregulation in Cerebral Microvascular Endothelial Cells via MAPK Signaling and Augmenting MMP-2 Levels. Oxid Med Cell Longev (2015) 2015: 120641. doi: 10.1155/2015/120641 26290681 PMC4531183 · DOI
  134. [177]Vandenbroucke RE Dejonckheere E Van Lint P Demeestere D Van Wonterghem E Vanlaere I. Matrix Metalloprotease 8-Dependent Extracellular Matrix Cleavage at the Blood-CSF Barrier Contributes to Lethality During Systemic Inflammatory Diseases. J Neurosci (2012) 32: 9805–16. doi: 10.1523/JNEUROSCI.0967-12.2012 PMC6621276 22815495 · DOI
  135. [178]Yu HY Cai YB Lu Z. Activation of AMPK Improves Lipopolysaccharide-Induced Dysfunction of the Blood-Brain Barrier in Mice. Brain Inj (2015) 29: 777–84. doi: 10.3109/02699052.2015.1004746 25794165 · DOI
  136. [179]Doll DN Hu H Sun JH Lewis SE Simpkins JW Ren XF. Mitochondrial Crisis in Cerebrovascular Endothelial Cells Opens the Blood-Brain Barrier. Stroke (2015) 46: 1681–9. doi: 10.1161/Strokeaha.115.009099 PMC4418219 25922503 · DOI · Paper page
  137. [180]Ma FF Zhang XJ Yin KJ. MicroRNAs in Central Nervous System Diseases: A Prospective Role in Regulating Blood-Brain Barrier Integrity. Exp Neurol (2020) 323: 113094. doi: 10.1016/j.expneurol.2019.113094 31676317 PMC7304262 · DOI
  138. [181]Lopez-Ramirez MA Wu D Pryce G Simpson JE Reijerkerk A King-Robson J. MicroRNA-155 Negatively Affects Blood-Brain Barrier Function During Neuroinflammation. FASEB J (2014) 28: 2551–65. doi: 10.1096/fj.13-248880 24604078 · DOI
  139. [182]Abbott NJ. Astrocyte-Endothelial Interactions and Blood-Brain Barrier Permeability. J Anat (2002) 200: 629–38. doi: 10.1046/j.1469-7580.2002.00064.x PMC1570746 12162730 · DOI · Paper page
  140. [184]Biesmans S Meert TF Bouwknecht JA Acton PD Davoodi N De Haes P. Systemic Immune Activation Leads to Neuroinflammation and Sickness Behavior in Mice. Mediators Inflamm (2013) 2013: 271359. doi: 10.1155/2013/271359 23935246 PMC3723093 · DOI
  141. [185]Fan L Wang TL Chang LR Song YZ Wu Y Ma DQ. Systemic Inflammation Induces a Profound Long Term Brain Cell Injury in Rats. Acta Neurobiol Exp (Wars) (2014) 74: 298– 306. 25231849
  142. [187]Carvalho-Tavares J Hickey MJ Hutchison J Michaud J Sutcliffe IT Kubes P. A Role for Platelets and Endothelial Selectins in Tumor Necrosis Factor-Alpha-Induced Leukocyte Recruitment in the Brain Microvasculature. Circ Res (2000) 87: 1141–8. doi: 10.1161/01.Res.87.12.1141 11110771 · DOI
  143. [188]Chui R Dorovini-Zis K. Regulation of CCL2 and CCL3 Expression in Human Brain Endothelial Cells by Cytokines and Lipopolysaccharide. J Neuroinflamm (2010) 7: 1. doi: 10.1186/1742-2094-7-1 PMC2819252 20047691 · DOI
  144. [189]Agrawal S Anderson P Durbeej M van Rooijen N Ivars F Opdenakker G. Dystroglycan Is Selectively Cleaved at the Parenchymal Basement Membrane at Sites of Leukocyte Extravasation in Experimental Autoimmune Encephalomyelitis. J Exp Med (2006) 203: 1007–19. doi: 10.1084/jem.20051342 PMC2118280 16585265 · DOI · Paper page
  145. [190]Pieper C Pieloch P Galla HJ. Pericytes Support Neutrophil Transmigration via Interleukin-8 Across a Porcine Co-Culture Model of the Blood-Brain Barrier. Brain Res (2013) 1524: 1– 11. doi: 10.1016/j.brainres.2013.05.047 23769734 · DOI
  146. [191]Hartz AMS Bauer B Fricker G Miller DS. Rapid Modulation of P-Glycoprotein-Mediated Transport at the Blood-Brain Barrier by Tumor Necrosis Factor-Alpha and Lipopolysaccharide. Mol Pharmacol (2006) 69: 462–70. doi: 10.1124/mol.105.017954 16278373 · DOI
  147. [192]Osburg B Peiser C Domling D Schomburg L Ko YT Voigt K. Effect of Endotoxin on Expression of TNF Receptors and Transport of TNF-Alpha at the Blood-Brain Barrier of the Rat. Am J Physiol Endocrinol Metab (2002) 283: E899–908. doi: 10.1152/ajpendo.00436.2001 12376316 · DOI
  148. [193]Dohgu S Fleegal-DeMotta MA Banks WA. Lipopolysaccharide-Enhanced Transcellular Transport of HIV-1 Across the Blood-Brain Barrier Is Mediated by Luminal Microvessel IL-6 and GM-CSF. J Neuroinflamm (2011) 8: 167. doi: 10.1186/1742-2094-8-167 PMC3260201 22129063 · DOI
  149. [194]Brkic M Balusu S Van Wonterghem E Gorle N Benilova I Kremer A. Amyloid Beta Oligomers Disrupt Blood-CSF Barrier Integrity by Activating Matrix Metalloproteinases. J Neurosci (2015) 35: 12766–78. doi: 10.1523/JNEUROSCI.0006-15.2015 PMC6795210 26377465 · DOI
  150. [195]Vandendriessche C Balusu S Van Cauwenberghe C Brkic M Pauwels M Plehiers N. Importance of Extracellular Vesicle Secretion at the Blood-Cerebrospinal Fluid Interface in the Pathogenesis of Alzheimer’s Disease. Acta Neuropathol Commun (2021) 9: 143. doi: 10.1186/s40478-021-01245-z 34425919 PMC8381545 · DOI
  151. [196]Steeland S Gorle N Vandendriessche C Balusu S Brkic M Van Cauwenberghe C. Counteracting the Effects of TNF Receptor-1 Has Therapeutic Potential in Alzheimer’s Disease. EMBO Mol Med (2018) 10: e8300. doi: 10.15252/emmm.201708300 29472246 PMC5887909 · DOI
  152. [198]Goehler LE Gaykema RP Hansen MK Anderson K Maier SF Watkins LR. Vagal Immune-to-Brain Communication: A Visceral Chemosensory Pathway. Auton Neurosci (2000) 85: 49– 59. doi: 10.1016/S1566-0702(00)00219-8 11189026 · DOI · Paper page
  153. [199]Fernandez R Nardocci G Navarro C Reyes EP Acuna-Castillo C Cortes PP. Neural Reflex Regulation of Systemic Inflammation: Potential New Targets for Sepsis Therapy. Front Physiol (2014) 5: 489. doi: 10.3389/fphys.2014.00489 25566088 PMC4266021 · DOI
  154. [200]Eyo UB Wu LJ. Bidirectional Microglia-Neuron Communication in the Healthy Brain. Neural Plast (2013) 2013: 456857. doi: 10.1155/2013/456857 24078884 PMC3775394 · DOI
  155. [201]Kaczmarczyk R Tejera D Simon BJ Heneka MT. Microglia Modulation Through External Vagus Nerve Stimulation in a Murine Model of Alzheimer’s Disease. J Neurochem (2018) 146: 76– 85. doi: 10.1111/jnc.14284 29266221 · DOI
  156. [203]Meneses G Bautista M Florentino A Diaz G Acero G Besedovsky H. Electric Stimulation of the Vagus Nerve Reduced Mouse Neuroinflammation Induced by Lipopolysaccharide. J Inflamm Lond (2016) 13: 33. doi: 10.1186/s12950-016-0140-5 27807399 PMC5086408 · DOI · Paper page
  157. [204]Riazi K Galic MA Kuzmiski JB Ho W Sharkey KA Pittman QJ. Microglial Activation and TNFalpha Production Mediate Altered CNS Excitability Following Peripheral Inflammation. Proc Natl Acad Sci USA (2008) 105: 17151–6. doi: 10.1073/pnas.0806682105 PMC2579393 18955701 · DOI · Paper page
  158. [205]Qin L He J Hanes RN Pluzarev O Hong JS Crews FT. Increased Systemic and Brain Cytokine Production and Neuroinflammation by Endotoxin Following Ethanol Treatment. J Neuroinflamm (2008) 5: 10. doi: 10.1186/1742-2094-5-10 PMC2373291 18348728 · DOI · Paper page
  159. [206]Kowalski K Mulak A. Brain-Gut-Microbiota Axis in Alzheimer’s Disease. J Neurogastroenterol Motil (2019) 25: 48– 60. doi: 10.5056/jnm18087 30646475 PMC6326209 · DOI · Paper page
  160. [207]Wang C Klechikov AG Gharibyan AL Warmlander SKTS Jarvet J Zhao LN. The Role of Pro-Inflammatory S100A9 in Alzheimer’s Disease Amyloid-Neuroinflammatory Cascade. Acta Neuropathol (2014) 127: 507–22. doi: 10.1007/s00401-013-1208-4 PMC4148179 24240735 · DOI
  161. [208]Mogensen TH. Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses. Clin Microbiol Rev (2009) 22: 240–73. doi: 10.1128/CMR.00046-08 PMC2668232 19366914 · DOI
  162. [209]Erny D de Angelis ALH Jaitin D Wieghofer P Staszewski O David E. Host Microbiota Constantly Control Maturation and Function of Microglia in the CNS. Nat Neurosci (2015) 18: 965–77. doi: 10.1038/nn.4030 PMC5528863 26030851 · DOI · Paper page
  163. [210]Hoogland ICM Westhoff D Engelen-Lee JY Melief J Seron MV Houben-Weerts JHMP. Microglial Activation After Systemic Stimulation With Lipopolysaccharide and Escherichia Coil. Front Cell Neurosci (2018) 12: 110. doi: 10.3389/fncel.2018.00110 29755322 PMC5932388 · DOI
  164. [214]Kaparakis-Liaskos M Ferrero RL. Immune Modulation by Bacterial Outer Membrane Vesicles. Nat Rev Immunol (2015) 15: 375–87. doi: 10.1038/nri3837 25976515 · DOI
  165. [215]Aguayo S Schuh CMAP Vicente B Aguayo LG. Association Between Alzheimer’s Disease and Oral and Gut Microbiota: Are Pore Forming Proteins the Missing Link? J Alzheimers Dis (2018) 65: 29– 46. doi: 10.3233/Jad-180319 30040725 · DOI
  166. [216]Ismail S Hampton MB Keenan JI. Helicobacter Pylori Outer Membrane Vesicles Modulate Proliferation and Interleukin-8 Production by Gastric Epithelial Cells. Infect Immun (2003) 71: 5670–5. doi: 10.1128/iai.71.10.5670-5675.2003 PMC201067 14500487 · DOI
  167. [217]Han EC Choi SY Lee Y Park JW Hong SH Lee HJ. Extracellular RNAs in Periodontopathogenic Outer Membrane Vesicles Promote TNF-Alpha Production in Human Macrophages and Cross the Blood-Brain Barrier in Mice. FASEB J (2019) 33: 13412–22. doi: 10.1096/fj.201901575R PMC6894046 31545910 · DOI
  168. [218]Wei SC Peng WJ Mai YR Li KL Wei W Hu L. Outer Membrane Vesicles Enhance Tau Phosphorylation and Contribute to Cognitive Impairment. J Cell Physiol (2020) 235: 4843–55. doi: 10.1002/jcp.29362 31663118 · DOI

Cited by

Sorted by citations

Authors
Xie, J., Van Hoecke, L., & Vandenbroucke, R. E.
Affiliations
Ghent University (BE)
Corresponding author
Vandenbroucke, Roosmarijn E.
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-01-06
Volume
12
Pages
796867-796867
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2021.796867
PMC
PMC8770958
OpenAlex
W4205125680
Cited by
324
References
51
Citations by year
2026: 58 · 2025: 90 · 2024: 96 · 2023: 56 · 2022: 24
FWCI
9.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fonds Wetenschappelijk Onderzoek (G055121N)
  • China Scholarship Council (201808360194)
  • Vlaamse regering
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, systemic inflammation, peripheral inflammation, gut-brain axis, intestinal inflammation, neuroinflammation, pathogenesis, disease progression, therapeutic target
MeSH terms
Brain-Gut Axis, Alzheimer Disease, Animals, Biological Transport, Blood-Brain Barrier, Brain, Disease Models, Animal, Disease Susceptibility, Environment, Humans, Inflammation, Signal Transduction, Biomarkers, Host-Pathogen Interactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review