CoChat
Sign Up
Cited by 46Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsAnesthesia and Neurotoxicity Research

Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer’s disease

Open access
Basak, Jacob M., Ferreiro, Aura, Cohen, Lucy S., Sheehan, Patrick W., Nadarajah, Collin J., Kanan, Michael F., Sukhum, Kimberley V., Dantas, Gautam +1 more·2021·Neurobiology of Disease
DOI 10.1016/j.nbd.2021.105292PMC PMC8057119
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Sepsis, a leading cause for intensive care unit admissions, causes both an acute encephalopathy and chronic brain dysfunction in survivors. A history of sepsis is also a risk factor for future development of dementia symptoms. Similar neuropathologic changes are associated with the cognitive decline of sepsis and Alzheimer's disease (AD), including neuroinflammation, neuronal death, and synaptic loss. Amyloid plaque pathology is the earliest pathological hallmark of AD, appearing 10 to 20 years prior to cognitive decline, and is present in 30% of people over 65. As sepsis is also more common in older adults, we hypothesized that sepsis might exacerbate amyloid plaque deposition and plaque-related injury, promoting the progression of AD-related pathology. METHODS: We evaluated whether the brain's response to sepsis modulates AD-related neurodegenerative changes by driving amyloid deposition and neuroinflammation in mice. We induced polymicrobial sepsis by cecal ligation and puncture (CLP) in APP/PS1-21 mice, a model of AD-related β-amyloidosis. We performed CLP or sham surgery at plaque onset (2 months of age) and examined pathology 2 months after CLP in surviving mice. RESULTS: Sepsis significantly increased fibrillar amyloid plaque formation in the hippocampus of APP/PS1-21 mice. Sepsis enhanced plaque-related astrocyte activation and complement C4b gene expression in the brain, both of which may play a role in modulating amyloid formation. CLP also caused large scale changes in the gut microbiome of APP/PS1 mice, which have been associated with a pro-amyloidogenic and neuroinflammatory state. CONCLUSIONS: Our results suggest that experimental sepsis can exacerbate amyloid plaque deposition and plaque-related inflammation, providing a potential mechanism for increased dementia in older sepsis survivors.

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 · 10.1016/j.nbd.2021.105292

Cites

9 of 9 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?

  • In mouse models of β-amyloidosis, experimental sepsis was shown to increase the formation of fibrillar amyloid plaques, promote neuroinflammation, and exacerbate cognitive impairment.

    “In mouse models of β-amyloidosis, experimental sepsis was shown to increase the formation of fibrillar amyloid plaques, promote neuroinflammation, and exacerbate cognitive impairment [101].”

    From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [101]

    The Abstract Results and Discussion report increased hippocampal fibrillar amyloid plaques and plaque-related neuroinflammation after experimental sepsis in APP/PS1 mice. They do not report that sepsis exacerbated cognitive impairment in those mice; the Discussion presents accelerated symptomatic decline as a possibility, not a measured result. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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: 55

  1. [1]Pandharipande PP, Girard TD, Jackson JC, Morandi A, Thompson JL, Pun BT, Long-term cognitive impairment after critical illness. N Engl J Med. 2013; 369(14): 1306– 16. 24088092 PMC3922401
  2. [2]Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, and Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016; 2: 16045. 28117397 PMC5538252
  3. [5]Iwashyna TJ, Cooke CR, Wunsch H, and Kahn JM. Population burden of long-term survivorship after severe sepsis in older Americans. J Am Geriatr Soc. 2012; 60(6): 1070– 7. 22642542 PMC3374893
  4. [6]Semmler A, Widmann CN, Okulla T, Urbach H, Kaiser M, Widman G, Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry. 2013; 84(1): 62– 9. 23134661
  5. [7]Widmann CN, and Heneka MT. Long-term cerebral consequences of sepsis. Lancet Neurol. 2014; 13(6): 630– 6. 24849863
  6. [8]Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep. 2019; 9(1): 5790. 30962497 PMC6453933
  7. [9]Skelly DT, Hennessy E, Dansereau MA, and Cunningham C. A systematic analysis of the peripheral and CNS effects of systemic LPS, IL-1beta, [corrected] TNF-alpha and IL-6 challenges in C57BL/6 mice. PLoS One. 2013; 8(7): e69123. 23840908 PMC3698075
  8. [10]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(1): 226– 44. 29127203 PMC5766916
  9. [11]Erickson MA, and Banks WA. Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav Immun. 2011; 25(8): 1637– 48. 21704698 PMC3389494
  10. [12]Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation. 2008; 5: 38. 18793399 PMC2553764
  11. [13]Aguilar-Valles A, Kim J, Jung S, Woodside B, and Luheshi GN. Role of brain transmigrating neutrophils in depression-like behavior during systemic infection. Mol Psychiatry. 2014; 19(5): 599– 606. 24126927
  12. [14]Michels M, Vieira AS, Vuolo F, Zapelini HG, Mendonca B, Mina F, The role of microglia activation in the development of sepsis-induced long-term cognitive impairment. Brain Behav Immun. 2015; 43: 54– 9. 25019583
  13. [16]Hofer S, Bopp C, Hoerner C, Plaschke K, Faden RM, Martin E, Injury of the blood brain barrier and up-regulation of icam-1 in polymicrobial sepsis. J Surg Res. 2008; 146(2): 276– 81. 18164036
  14. [17]Banks WA, Gray AM, Erickson MA, Salameh TS, Damodarasamy M, Sheibani N, Lipopolysaccharide-induced blood-brain barrier disruption: roles of cyclooxygenase, oxidative stress, neuroinflammation, and elements of the neurovascular unit. J Neuroinflammation. 2015; 12: 223. 26608623 PMC4660627
  15. [18]Bozza FA, Garteiser P, Oliveira MF, Doblas S, Cranford R, Saunders D, Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab. 2010; 30(2): 440– 8. 19844239 PMC2949132
  16. [19]Barichello T, Fortunato JJ, Vitali AM, Feier G, Reinke A, Moreira JC, Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med. 2006; 34(3): 886– 9. 16505668
  17. [20]Hippensteel JA, Anderson BJ, Orfila JE, McMurtry SA, Dietz RM, Su G, Circulating heparan sulfate fragments mediate septic cognitive dysfunction. J Clin Invest. 2019; 129(4): 1779– 84. 30720464 PMC6436867
  18. [21]Zaghloul N, Addorisio ME, Silverman HA, Patel HL, Valdes-Ferrer SI, Ayasolla KR, Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors. Front Immunol. 2017; 8: 1673. 29326685 PMC5736570
  19. [22]Semmler A, Frisch C, Debeir T, Ramanathan M, Okulla T, Klockgether T, Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol. 2007; 204(2): 733– 40. 17306796
  20. [23]Singer BH, Newstead MW, Zeng X, Cooke CL, Thompson RC, Singer K, Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation. PLoS One. 2016; 11(2): e0149136. 26862765 PMC4749127
  21. [24]Holtzman DM, Morris JC, and Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011; 3(77): 77sr1. 21471435 PMC3130546
  22. [25]Selkoe DJ, and Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016; 8(6): 595– 608. 27025652 PMC4888851
  23. [26]Jack CR Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010; 9(1): 119– 28. 20083042 PMC2819840
  24. [27]Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008; 65(11): 1509– 17. 19001171 PMC2636844
  25. [29]Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ, Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol. 2003; 62(11): 1087– 95. 14656067
  26. [30]Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010; 184(7): 3768– 79. 20200277 PMC2914630
  27. [31]Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J. 2012; 6(8): 1621– 4. 22402401 PMC3400413
  28. [32]Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, and Holmes SP. DADA2: High-resolution sample inference from Illumina amplicon data. Nat Methods. 2016; 13(7): 581– 3. 27214047 PMC4927377
  29. [33]Wright ES. DECIPHER: harnessing local sequence context to improve protein multiple sequence alignment. BMC Bioinformatics. 2015; 16: 322. 26445311 PMC4595117
  30. [34]Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013; 41(Database issue): D590– 6. 23193283 PMC3531112
  31. [35]McMurdie PJ, and Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One. 2013; 8(4): e61217. 23630581 PMC3632530
  32. [36]Segata N, Izard J, Waldron L, Gevers D, Miropolsky L, Garrett WS, Metagenomic biomarker discovery and explanation. Genome Biol. 2011; 12(6): R60. 21702898 PMC3218848
  33. [37]Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 2006; 7(9): 940– 6. 16906128 PMC1559665
  34. [38]Ikonomovic MD, Abrahamson EE, Isanski BA, Debnath ML, Mathis CA, Dekosky ST, X-34 labeling of abnormal protein aggregates during the progression of Alzheimer’s disease. Methods Enzymol. 2006; 412: 123– 44. 17046656
  35. [39]Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nature medicine. 2020; 26(1): 131– 42. PMC6980793 31932797
  36. [40]Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, Interferon-gamma and tumor necrosis factor-alpha regulate amyloid-beta plaque deposition and beta-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol. 2007; 170(2): 680– 92. 17255335 PMC1851864
  37. [41]Avramovich Y, Amit T, and Youdim MB. Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein. J Biol Chem. 2002; 277(35): 31466– 73. 12070143
  38. [42]Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, van Leuven F, Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci. 2003; 23(30): 9796– 804. 14586007 PMC6740896
  39. [43]Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015; 14(4): 388– 405. 25792098 PMC5909703
  40. [45]Davis EJ, Foster TD, and Thomas WE. Cellular forms and functions of brain microglia. Brain Res Bull. 1994; 34(1): 73– 8. 8193937
  41. [46]Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017; 169(7): 1276– 90.e17. 28602351
  42. [48]Minter MR, Hinterleitner R, Meisel M, Zhang C, Leone V, Zhang X, Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1DeltaE9 murine model of Alzheimer’s disease. Sci Rep. 2017; 7(1): 10411. 28874832 PMC5585265
  43. [50]Singer BH, Dickson RP, Denstaedt SJ, Newstead MW, Kim K, Falkowski NR, Bacterial Dissemination to the Brain in Sepsis. Am J Respir Crit Care Med. 2018; 197(6): 747– 56. 29232157 PMC5855074
  44. [51]Sonneville R, Verdonk F, Rauturier C, Klein IF, Wolff M, Annane D, Understanding brain dysfunction in sepsis. Ann Intensive Care. 2013; 3(1): 15. 23718252 PMC3673822
  45. [52]Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013; 12(4): 357– 67. 23477989
  46. [53]Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012; 367(9): 795– 804. 22784036 PMC3474597
  47. [54]Jack CR Jr., Therneau TM, Weigand SD, Wiste HJ, Knopman DS, Vemuri P, Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging-Alzheimer’s Association Research Framework. JAMA Neurol. 2019. PMC6632154 31305929
  48. [55]Brookmeyer R, Abdalla N, Kawas CH, and Corrada MM. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2018; 14(2): 121– 9. 29233480 PMC5803316
  49. [56]Martin GS, Mannino DM, and Moss M. The effect of age on the development and outcome of adult sepsis. Crit Care Med. 2006; 34(1): 15– 21. 16374151
  50. [58]Tejera D, Mercan D, Sanchez-Caro JM, Hanan M, Greenberg D, Soreq H, Systemic inflammation impairs microglial Abeta clearance through NLRP3 inflammasome. Embo j. 2019; 38(17): e101064. 31359456 PMC6717897
  51. [59]Wang X, Sun G, Feng T, Zhang J, Huang X, Wang T, Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression. Cell Res. 2019; 29(10): 787– 803. 31488882 PMC6796854
  52. [61]Dodiya HB, Frith M, Sidebottom A, Cao Y, Koval J, Chang E, Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1–21 Alzheimer’s transgenic mice. Sci Rep. 2020; 10(1): 8183. 32424118 PMC7235236
  53. [62]Shin NR, Whon TW, and Bae JW. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 2015; 33(9): 496– 503. 26210164
  54. [63]Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016; 8(340): 340ra72. PMC5505565 27225182
  55. [64]Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010; 5(3): e9505. 20209079 PMC2831066

Cited by

Sorted by citations

Authors
Basak, J. M., Ferreiro, A., Cohen, L. S., Sheehan, P. W., Nadarajah, C. J., Kanan, M. F., Sukhum, K. V., Dantas, G., & Musiek, E. S.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Musiek, Erik S.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2021-05
Volume
152
Pages
105292
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2021.105292
PMC
PMC8057119
OpenAlex
W3126930327
Cited by
46
References
9
Citations by year
2026: 8 · 2025: 11 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 1
FWCI
4.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
NIA
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
Keywords
sepsis, Alzheimer's disease, amyloid plaques, neuroinflammation, hippocampus, APP/PS1 mice, cecal ligation and puncture, polymicrobial sepsis, astrocyte activation, complement C4B, gut microbiota, dementia, beta-amyloidosis
MeSH terms
Gastrointestinal Microbiome, Neuroinflammatory Diseases, Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Sepsis, Mice, Plaque, Amyloid

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