APOε4 is associated with enhanced in vivo innate immune responses in human subjects
Open accessAbstract
Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined.Objective We sought to define the relationship of APOε4 to the human innate immune response.Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity.Results Whole blood from healthy APOε3/APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3/APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3/APOε3 and APOε3/APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe-deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients.Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
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.
Integrity signals
Registry
Cites
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.
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?
Prior work shows that E4 impairs microglial metabolism/immune reactivity and can exaggerate cytokine reactivity to LPS.
“Prior work shows that E4 impairs microglial metabolism/immune reactivity and can exaggerate cytokine reactivity to LPS”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Gale et al., 2014
The Results section reports higher TNFα after LPS challenge in human APOε4 carriers and APOE4-targeted mice, supporting exaggerated cytokine reactivity to LPS. The paper’s reported experiments concern blood responses and systemic inflammation; our copy does not establish that E4 impairs microglial metabolism or microglial immune reactivity. Page numbers are unavailable in the indexed copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE genotype influences the inflammatory response, with E4 expression linked to significantly higher cytokine levels in both humans and mice compared to E3 or E2.
“In addition to metabolic dysregulation, APOE genotype also influences the inflammatory response, with E4 expression linked to significantly higher cytokine levels in both humans and mice compared to E3 or E2”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Gale et al., 2014
The Results report higher cytokine responses in APOε3/APOε4 humans than APOε3/APOε3 humans after specified immune challenges, and higher plasma TNFα and G-CSF in LPS-challenged APOE4 mice than APOE3 mice. The study does not establish higher cytokine levels relative to APOE2 in either species; it also reports that some cytokine responses were similar between the E4 and E3 groups. (LLM, conf=0.90)
Experimental — accuracy not yet measuredComparable findings have been reported following intraperitoneal LPS injection.
“and comparable findings have been reported following intraperitoneal LPS injection”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Gale et al., 2014
The APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer's disease.
“the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [83]
Humans with the APOE4 variant are more sensitive to injected LPS than those with APOE3, and mice with endogenous ApoE replaced with APOE4 are more sensitive to LPS than those replaced with APOE3.
“Humans with the APOE4 variant are more sensitive to injected LPS than those with APOE3, and similarly, mice with endogenous ApoE replaced with APOE4 are more sensitive to LPS than those replaced with APOE3 [83].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [83]
There is a clear and direct link between APOE variants and endotoxin.
“Thus, there is a clear and direct link between APOE variants and endotoxin.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [83]
APOE ε4 carriers have a stronger systemic inflammatory response to intravenous LPS challenge, including more intense hyperthermia and higher TNF secretion in whole blood.
“APOE ε4 carriers have a stronger systemic inflammatory response to an intravenous LPS challenge, including more intense hyperthermia and higher levels of TNF secretion in whole blood”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Gale et al., 2014
In healthy humans challenged with intravenous LPS infusion, ε4-carriers demonstrate significantly higher elevation of body temperature and plasma TNF levels compared to ε4 non-carriers.
“In healthy humans challenged with intravenous LPS infusion, ε4-carriers demonstrate significantly higher elevation of body temperature and plasma TNF levels compared to ε4 non-carriers108.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [108]
A greater immune response associated with the ε4 allele is also observed in human APOE-TR mice and in cultured microglia/macrophages upon LPS stimulation.
“A greater immune response associated with the ε4 allele is also observed in human ApoE-targeted replacement (APOE-TR) mice [G] and in cultured microglia/macrophages upon LPS stimulation108–110.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [108]
When whole blood isolates from human subjects were stimulated ex vivo with TLR ligands, enhanced production of cytokines and chemokines was observed in blood from ε4+ donors compared with ε4− donors.
“Similarly, when whole blood isolates from human subjects were stimulated ex vivo with TLR ligands, enhanced production of a wide panel of cytokines and chemokines was observed in blood from ε4+ donors compared with ε4− donors108.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [108]
ApoE4 is less effective than ApoE3 in inducing cholesterol efflux from macrophages, causing cholesterol accumulation on cell membranes.
“ApoE4 is reported to be less effective than ApoE3 in inducing cholesterol efflux from macrophages114, which causes cholesterol accumulation on cell membranes108,114.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [108]
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
Inference of Population Structure Using Multilocus Genotype Data
Pritchard, J. K., Stephens, M., & Donnelly, P. (2000) · Genetics · doi:10.1093/genetics/155.2.945 · Cited by 33,871 · see citing works
Knaus, W. A., Draper, E. A., Wagner, D. P., & Zimmerman, J. E. (1985) · Critical Care Medicine · doi:10.1097/00003246-198510000-00009 · Cited by 15,333 · see citing works
APACHE II-A Severity of Disease Classification System
Knaus, W. A., Draper, E. A., Wagner, D. P., & Zimmerman, J. E. (1986) · Critical Care Medicine · doi:10.1097/00003246-198608000-00028 · Cited by 13,379 · see citing works
Bone, R. C., BALK, R. A., Cerra, F. B., Dellinger, R. P., Fein, A. M., Knaus, W. A., Schein, R. M. H., & Sibbald, W. J. (1992) · CHEST Journal · doi:10.1378/chest.101.6.1644 · Cited by 13,192 · see citing works
Bernard, G. R., Artigas, A., Brigham, K. L., Carlet, J., Falke, K., Hudson, L., Lamy, M., Legall, J. R., Morris, A., & Spragg, R. (1994) · American journal of respiratory and critical care medicine · doi:10.1164/ajrccm.149.3.7509706 · Cited by 6,746 · see citing works
APACHE II: a severity of disease classification system.
Knaus, W. A., Draper, E. S., Wagner, D. P., & Zimmerman, J. E. (1985) · PubMed · Cited by 6,034 · see citing works
American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference
(1992) · Critical Care Medicine · doi:10.1097/00003246-199206000-00025 · Cited by 5,091 · see citing works
Anderson, E. N. (1977) · Journal of California Anthropology, The · Cited by 2,550 · see citing works
Toll-like Receptor-4 Mediates Lipopolysaccharide-induced Signal Transduction
Chow, J. C., Young, D. W., Golenbock, D. T., Christ, W. J., & Gusovsky, F. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.16.10689 · Cited by 1,924 · see citing works
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Cutting Edge: Role of Toll-Like Receptor 1 in Mediating Immune Response to Microbial Lipoproteins
Takeuchi, O., Sato, S., Horiuchi, T., Hoshino, K., Takeda, K., Dong, Z., Modlin, R. L., & Akira, S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.1.10 · Cited by 1,328 · see citing works
Kawai, T., Takeuchi, O., Fujita, T., Inoue, J., Mühlradt, P. F., Sato, S., Hoshino, K., & Akira, S. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.10.5887 · Cited by 1,095 · see citing works
Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E
Huo, Y., Schober, A., Forlow, S. B., Smith, D. F., Hyman, M. C., Jung, S., Littman, D. R., Weber, C., & Ley, K. F. (2002) · Nature Medicine · doi:10.1038/nm810 · Cited by 1,008 · see citing works
Tang, M.-X. (1998) · JAMA · doi:10.1001/jama.279.10.751 · Cited by 771 · see citing works
Apolipoprotein E structure: insights into function
Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.06.008 · Cited by 583 · see citing works
Murphy, A. J., Akhtari, M., Tolani, S., Pagler, T., Bijl, N., Kuo, C.-L., Wang, M., Sanson, M., Abramowicz, S., Welch, C., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57559 · Cited by 521 · see citing works
Apolipoprotein E Induces Antiinflammatory Phenotype in Macrophages
Baitsch, D., Bock, H. H., Engel, T., Telgmann, R., Müller‐Tidow, C., Varga, G., Bot, M., Herz, J., Robenek, H., von Eckardstein, A., et al. (2011) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.111.222745 · Cited by 361 · see citing works
Sepsis, thrombosis and organ dysfunction
Semeraro, N., Ammollo, C. T., Semeraro, F., & Colucci, M. (2011) · Thrombosis Research · doi:10.1016/j.thromres.2011.10.013 · Cited by 331 · see citing works
Dong, L. M., Wilson, C., Wardell, M. R., Simmons, T., Mahley, R. W., Weisgraber, K. H., & Agard, D. A. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31797-0 · Cited by 320 · see citing works
ENDOTOXAEMIA: AN EARLY PREDICTOR OF SEPTICAEMIA IN FEBRILE PATIENTS
van Deventer, S. J. H., ten Cate, J., Buller, H., Sturk, A., & Pauw, W. (1988) · The Lancet · doi:10.1016/s0140-6736(88)91412-2 · Cited by 316 · see citing works
Platelets and the innate immune system: mechanisms of bacterial‐induced platelet activation
Cox, D. M., Kerrigan, S. W., & Watson, S. P. (2011) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2011.04264.x · Cited by 315 · see citing works
PROGNOSTICATION IN RHEUMATOID ARTHRITIS
(1980) · The Lancet · doi:10.1016/s0140-6736(80)90724-2 · Cited by 288 · see citing works
Platelet Counts Differ by Sex, Ethnicity, and Age in the United States
Segal, J. B., & Moliterno, A. R. (2005) · Annals of Epidemiology · doi:10.1016/j.annepidem.2005.06.052 · Cited by 278 · see citing works
Fessler, M. B., & Parks, J. S. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100253 · Cited by 270 · see citing works
Self-citationToll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis
Wurfel, M. M., Gordon, A. C., Holden, T. D., Radella, F., Strout, J., Kajikawa, O., Ruzinski, J. T., Rona, G., Black, A. R., Stratton, S., et al. (2008) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200803-462oc · Cited by 244 · see citing works
Self-citationCD14 is a coreceptor of Toll-like receptors 7 and 9
Baumann, C., Aspalter, I. M., Sharif, O., Pichlmair, A., Blüml, S., Grebien, F., Brückner, M., Pasierbek, P., Aumayr, K., Planyavsky, M., et al. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20101111 · Cited by 220 · see citing works
Apolipoprotein E Inhibits Platelet Aggregation through the L-Arginine:Nitric Oxide Pathway
Riddell, D. R., Graham, A., & Owen, J. S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.1.89 · Cited by 209 · see citing works
Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c
Edelstein, L. C., Simon, L. M., Montoya, R. T., Holinstat, M. A., Chen, E. S., Bergeron, A. L., Kong, X., Nagalla, S., Mohandas, N., Cohen, D. E., et al. (2013) · Nature Medicine · doi:10.1038/nm.3385 · Cited by 208 · see citing works
Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis
Murphy, A. J., Bijl, N., Yvan‐Charvet, L., Welch, C. L., Bhagwat, N., Adili, R., Wang, Y., Shaw, J. A., Levine, R. L., Ni, H., et al. (2013) · Nature Medicine · doi:10.1038/nm.3150 · Cited by 198 · see citing works
Roselaar, S. E., & Daugherty, A. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32160-x · Cited by 193 · see citing works
Apolipoprotein E Protects Against Bacterial Lipopolysaccharide-induced Lethality
Van Oosten, M., Rensen, P. C. N., Van Amersfoort, E. S., Van Eck, M., Van Dam, A.-M., Brevé, J. J. P., Vogel, T., Panet, A., Van Berkel, T. J. C., & Kuiper, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009915200 · Cited by 186 · see citing works
HUMAN ENDOTOXEMIA: A MODEL FOR MECHANISTIC INSIGHT AND THERAPEUTIC TARGETING
Lowry, S. F. (2005) · Shock · doi:10.1097/01.shk.0000191340.23907.a1 · Cited by 157 · see citing works
Self-citationNovel Polymorphisms in the Myosin Light Chain Kinase Gene Confer Risk for Acute Lung Injury
Gao, L., Grant, A. V., Halder, I., Brower, R. G., Sevransky, J., Maloney, J. P., Moss, M. M., Shanholtz, C. B., Yates, C. R., Meduri, G. U., et al. (2006) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2005-0404oc · Cited by 151 · see citing works
Self-citationRensen, P. C., Oosten, M., Bilt, E., Eck, M., Kuiper, J., & Berkel, T. J. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119427 · Cited by 113 · see citing works
Deo, R. C., Reich, D., Tandon, A., Akylbekova, E. L., Patterson, N. J., Waliszewska, A., Kathiresan, S., Sarpong, D. F., Taylor, H. A., & Wilson, J. G. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000342 · Cited by 111 · see citing works
Qayyum, R., Snively, B. M., Ziv, E., Nalls, M. A., Liu, Y., Tang, W., Yanek, L. R., Lange, L. A., Evans, M. K., Ganesh, S. K., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002491 · Cited by 107 · see citing works
Effects of apoE genotype on macrophage inflammation and heme oxygenase-1 expression
Jofre‐Monseny, L., Łoboda, A., Wagner, A. E., Huebbe, P., Boesch, C., Józkowicz, A., Minihane, A. M., Dulak, J., & Rimbach, G. H. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.03.150 · Cited by 106 · see citing works
Apolipoprotein E genotype and hepatitis C, HIV and herpes simplex disease risk: a literature review
Kuhlmann, I., Minihane, A. M., Huebbe, P., Nebel, A., & Rimbach, G. H. (2010) · Lipids in Health and Disease · doi:10.1186/1476-511x-9-8 · Cited by 106 · see citing works
Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice
Dole, V. S., Matuskova, J., Vasile, E., Yesilaltay, A., Bergmeier, W., Bernimoulin, M. P., Wagner, D. D., & Krieger, M. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.162347 · Cited by 82 · see citing works
Merrick, B. A., Dhungana, S., Williams, J. G., et al. (2011) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m110.006007 · Cited by 80 · see citing works
Singh, K., Chaturvedi, R., Barry, D. P., Coburn, L. A., Asim, M., Lewis, N. D., Piazuelo, M. B., Washington, M. K., Vitek, M. P., & Wilson, K. T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.176719 · Cited by 76 · see citing works
Scavenger receptor BI modulates platelet reactivity and thrombosis in dyslipidemia
Ma, Y., Ashraf, M. Z., & Podrez, E. A. (2010) · Blood · doi:10.1182/blood-2010-02-268508 · Cited by 72 · see citing works
Apolipoprotein E‐deficient mice have an impaired immune response to Klebsiella pneumoniae
Bont, D., Netea, Demacker, Kullberg, Meer, V. D., & Stalenhoef (2000) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2000.00715.x · Cited by 71 · see citing works
Chang, M., Yesupriya, A., Ned, R. M., Mueller, P. W., & Dowling, N. F. (2010) · BMC Medical Genetics · doi:10.1186/1471-2350-11-62 · Cited by 64 · see citing works
Janot, L., Sécher, T., Torres, D., Maillet, I., Pfeilschifter, J. M., Quesniaux, V. F. J., Landmann, R. M., Ryffel, B., & Erard, F. (2008) · The Journal of Infectious Diseases · doi:10.1086/588815 · Cited by 64 · see citing works
Grocott, H. P., Newman, M. F., El-Moalem, H. E., et al. (2001) · Journal of Thoracic and Cardiovascular Surgery · doi:10.1067/mtc.2001.115152 · Cited by 63 · see citing works
Differences in the Association Between Apolipoprotein E Genotype and Mortality Across Populations
Ewbank, D. (2007) · The Journals of Gerontology Series A · doi:10.1093/gerona/62.8.899 · Cited by 47 · see citing works
Madenspacher, J. H., Azzam, K. M., Gong, W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.377192 · Cited by 41 · see citing works
Self-citationAPOE Genotype Affects Outcome in a Murine Model of Sepsis: Implications for a New Treatment Strategy
Wang, H., Christensen, D. J., Vitek, M. P., Sullivan, P. M., & Laskowitz, D. T. (2009) · Anaesthesia and Intensive Care · doi:10.1177/0310057x0903700111 · Cited by 34 · see citing works
L-4F Alters Hyperlipidemic (But Not Healthy) Mouse Plasma to Reduce Platelet Aggregation
Buga, G. M., Navab, M., Imaizumi, S., Reddy, S. T., Yekta, B., Hough, G., Chanslor, S., Anantharamaiah, G. M., & Fogelman, A. M. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.200162 · Cited by 29 · see citing works
Okoro, E. U., Zhao, Y., Guo, Z., Zhou, L., Lin, X., & Yang, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044430 · Cited by 25 · see citing works
Apolipoprotein E genotype is related to nitric oxide production in platelets
Marcourakis, T., Bahia, V. S., Kawamoto, E. M., Munhoz, C. D., Gorjão, R., Artes, R., Kok, F., Caramelli, P., Nitríni, R., Curi, R., et al. (2008) · Cell Biochemistry and Function · doi:10.1002/cbf.1516 · Cited by 19 · see citing works
Chulada, P. C., Vainorius, E., Garantziotis, S., Burch, L. H., Blackshear, P. J., & Zeldin, D. C. (2011) · Environmental Health Perspectives · doi:10.1289/ehp.1003348 · Cited by 14 · see citing works
Self-citationDong, A., Caicedo, J., Han, S. G., Mueller, P., Saha, S. P., Smyth, S. S., & Gairola, C. G. (2010) · Thrombosis Research · doi:10.1016/j.thromres.2010.03.010 · Cited by 13 · see citing works
Öztürk, Z., Enkhmaa, B., Shachter, N. S., Berglund, L., & Anuurad, E. (2010) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2010.0034 · Cited by 9 · see citing works
Organ dysfunction scores in critical illness
Vincent, J. (2005) · Journal of Organ Dysfunction · doi:10.1080/17471060500229321 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220 · see citing works
Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight
Shi, Y., & Holtzman, D. M. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0051-1 · Cited by 595 · see citing works
A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward
Belloy, M. E., Napolioni, V., & Greicius, M. D. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.056 · Cited by 570 · see citing works
Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model
Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., Hoyle, R., & Holtzman, D. M. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20190980 · Cited by 448 · see citing works
The endotoxin hypothesis of neurodegeneration
Brown, G. C. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1564-7 · Cited by 457 · see citing works
Harris, S. A., & Harris, E. A. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142853 · Cited by 279 · see citing works
Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277 · see citing works
Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms
Koutsodendris, N., Nelson, M. R., Rao, A., & Huang, Y. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-030421-112756 · Cited by 231 · see citing works
Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112196 · Cited by 203 · see citing works
Tai, L. M., Ghura, S., Koster, K. P., Liakaite, V., Maienschein‐Cline, M., Kanabar, P., Collins, N., Ben‐Aissa, M., Lei, A. Z., Bahroos, N., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13072 · Cited by 165 · see citing works
Inflammatory pathways in Alzheimer’s disease mediated by gut microbiota
Qian, X.-H., Song, X.-X., Liu, X.-L., Chen, S.-D., & Tang, H.-D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101317 · Cited by 153 · see citing works
Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits
Koutsodendris, N., Blumenfeld, J., Agrawal, A., Traglia, M., Grone, B., Zilberter, M., Yip, O., Rao, A., Nelson, M. R., Hao, Y., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00368-3 · Cited by 132 · see citing works
Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau
Rayaprolu, S., Higginbotham, L., Bagchi, P., Watson, C. M., Zhang, T., Levey, A. I., Rangaraju, S., & Seyfried, N. T. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-020-00840-3 · Cited by 118 · see citing works
Nelson, M. R., Liu, P., Agrawal, A., Yip, O., Blumenfeld, J., Traglia, M., Kim, M. J., Koutsodendris, N., Rao, A., Grone, B., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01480-8 · Cited by 118 · see citing works
The Interaction Between NF-κB and Estrogen in Alzheimer’s Disease
Mishra, P., Davies, D. A., & Albensi, B. C. (2023) · Molecular Neurobiology · doi:10.1007/s12035-022-03152-3 · Cited by 51 · see citing works
Albrecht, D. S., Sagare, A., Pachicano, M., Sweeney, M. D., Toga, A., Zlokovic, B., Chui, H., Joe, E., Schneider, L., Morris, J. C., et al. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.01.010 · Cited by 37 · see citing works
APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses
Friday, C. M., Stephens, I. O., Smith, C. T., Lee, S., Satish, D., Devanney, N. A., Cohen, S., Morganti, J. M., Gordon, S. M., & Johnson, L. A. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106983 · Cited by 33 · see citing works
Nolt, G. L., MacLean, S. M., Golden, L. R., Thorpe, S. P., Stephens, I. O., Funnell, J. L., Brock, C. R., Lucido, C. C., Smith, L., Hernandez, G., et al. (2027) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2026.08.005
- Authors
- Gale, S. C., Gao, L., Mikacenic, C., Coyle, S. M., Rafaels, N., Murray Dudenkov, T., Madenspacher, J. H., Draper, D. W., Ge, W., Aloor, J. J., Azzam, K. M., Lai, L., Blackshear, P. J., Calvano, S. E., Barnes, K. C., Lowry, S. F., Corbett, S., Wurfel, M. M., & Fessler, M. B.
- Affiliations
- Johns Hopkins University (US)
- University of Washington (US)
- National Institutes of Health (US)
- Corresponding author
- Fessler, Michael B.
- ORCID
- Venue
- Journal of Allergy and Clinical Immunology
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 134
- Issue
- 1
- Pages
- 127-134.e9
- ISSN
- 0091-6749 (ISSN-L)
- PMC
- PMC4125509
- OpenAlex
- W2110616131
- Cited by
- 202
- References
- 56
- Citations by year
- 2026: 24 · 2025: 20 · 2024: 12 · 2023: 20 · 2022: 19 · 2021: 29 · 2020: 19 · 2019: 16 · 2018: 12 · 2017: 9 · 2016: 10 · 2015: 12
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Allergy and Clinical Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5p50hl073994-05, 5r01gm034695-26)
- National Heart, Lung, and Blood Institute (P50 HL-073994, HL73994, R01HL089807)
- National Institute of General Medical Sciences (R01 GM-34695, R01 GM-034695)
- National Institute of Environmental Health Sciences (Z01ES102005, ZIAES102005)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- apolipoprotein E, APOE ε4, innate immunity, Toll-like receptors, lipopolysaccharide response, sepsis, organ damage, lipid rafts, monocytes, TNF-α, interleukin-6, coagulopathy, lymphocyte apoptosis, hyperthermia
- MeSH terms
- Adult, Animals, Cells, Cultured, Humans, Immunity, Innate, Ligands, Lipopolysaccharides, Mice, Transgenic, Monocytes, Tumor Necrosis Factor-alpha, Interleukin-6, Gene Expression, Sepsis, Toll-Like Receptor 2, Toll-Like Receptor 4, Toll-Like Receptor 5, Mice, Apolipoprotein E3, Apolipoprotein E4
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
