Neuronflammation; Complement; Alzheimer's Disease; Innate Immunity; Phagocytosis; Neurodegenerative Disorders
2019 Distinguished Professor, UCI
My laboratory is focused on the role of specific elements of the innate immune system in host defense and in maintaining a balance of protective responses in the host both in the periphery and the central nervous system. It is now being recognized that the nature of the first response to injury or invasion has significant influence in determining the nature of the subsequent responses including the adaptive immune response. That is, it is this first response that assesses the level of danger of a particular intrusion or injury and initiates a program of protection.
The current major research area in the lab is the investigation of the role of complement activation and subsequent inflammation in Alzheimer’s Disease. The neuropathological structures that are the hallmark of Alzheimer's disease (AD) include senile plaques composed of a proposed pathogenic peptide fragment, beta-amyloid, neurofibrillary tangles and loss of neurons. Using mouse models of AD, we have evidence consistent with the hypothesis that complement activation and subsequent inflammatory events contribute to the pathogenesis of dementia in AD, and are currently assessing the mechanism of action of candidate therapeutics to prevent or slow the progression of pathogenic events that lead to Alzheimer’s Disease in mouse models.
In addition, it is now acknowledged that early components of the complement system play a role in synaptic pruning during development and aging and disease. Furthermore, the complement component C1q is upregulated in response to injury and, independent of other complement components, can play a protective role in the early stages of disease by enhancing the clearance of cellular debris, altering the effects of the amyloid peptide on microglia, and/or providing direct neuroprotective effects. We use novel mouse models, RNA-Seq, confocal and super resolution microscopy and cell isolation procedures to assess the molecular basis of these effects and to verify strategic targets for therapeutic intervention in human neurodegenerative diseases.
"Host Defense Enhancement", Andrea J. Tenner and Ronald R. Nepomuceno, filed November 18, 1996, issued October 12, 1999. U.S. Patent # 5,965,439.
1994 AAAS Fellow
2005-06 UCI Emeritae/i Association Faculty Mentorship Award
2014-15 Daniel G. Aldrich, Jr. Distinguished University Service Award
2015 Society of Leukocyte Biology Honorary Life Member
2016 Hans J. Muller-Eberhard Distinguished Lecturer, Institute for Molecular
Medicine, University of Texas, Houston
2019 American Association of Immunologists Distinguished Lecturer
Garred, P., Tenner, A. J., and Mollnes, T.E. Therapeutic Targeting of the Complement System from Rare Diseases to Pandemics., Pharmacol. Reviews 73:792-827, 2021.
Markarian, M., Krattli, R. P., Baddour, J.D., Alikhani, L., Giedzinski, E., Usmani, M. T., Agrawal, A., Baulch, J. E., Tenner, A. J., and Acharya, M. M. Glia-selective deletion of complement C1q prevents radiation-induced cognitive deficits and neuroinflammation. Cancer Research DOI: 10.1158/0008-5472.CAN-20-2565, 2021.
Schartz, N.D. and Tenner, A. J. The Good, the Bad and the Opportunities of the Complement System in Neurodegenerative Disease, J. Neuroinflammation 17:354-378, 2020 (invited review) PMC7690210
Vitek, M. P., Araujo, J. A., Fossel, M., Greenberg, B. D., Howell, G. R., Sukoff Rizzo, S.J., Seyfried, N. T., Tenner, A. J., Territo, P.R., Windisch, M., Bain, L.J., Ross, A., Carrillo, M.C., Lamb, B.T., Edelmayer, R.M. Translational animal models for Alzheimer's disease: An Alzheimer's Association Business Consortium Think Tank. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2020;6:e12114. https://doi.org/10.1002/trc2.12114.
Tenner, A. J. Complement-Mediated Events in Alzheimer's Disease: Mechanisms and Potential Therapeutic Targets, J. Immunol. 204:306-315, 2020. PMC6951444
Oblak, A.L., Forner, S., Territo, P.R., Sasner, M., Carter, G.W., Howell, G.R., Sukoff-Rizzo, S.J., Logsdon B.A., Mangravite, L.M., Mortazavi, A., Baglietto-Vargas D., Green, K.N., MacGregor, G.R., Wood, M.A., Tenner, A.J., LaFerla,F.M., Lamb, B.T., and The MODEL-AD Consortium. Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease: MODEL-AD, Alzheimer's & Dementia: Translational Research & Clinical Interventions 6:e12110, 2020. PMC7683958
Bohlson, S. S., Garred, P., Kemper, C. and Tenner, A.J. Complement Nomenclature-Deconvoluted. Frontiers in Immunology 10:1-6, 2019.
Tenner, A. J., Stevens, B. and Woodruff, T. M., New Tricks for an Ancient System: Physiological and Pathological Roles of Complement in the CNS, Mol. Immunol. 102:3-13, 2018.
Crane, A., Brubaker, W.D., Johansson, J.U., Trigunaite, A., Ceballos, J., Bradt, B., Glavis-Bloom, C., Wallace, T.L., Tenner, A.J., and Rogers,J. Peripheral complement interactions with amyloid ß peptide (Aß) in Alzheimer's disease: 2. Relationship to Aß immunotherapy, Alzheimer’s and Dementia. 14:248-252, 2018. PMC5881571
Hernandez, M.X., Jiang, S. Cole,T.A., Chu, S-H, Fonseca, M.I., Fang, M.J., Hohsfield, L.A., Torres, M.D., Green, K.N., Wetsel, R.A., Mortazavi,A. and Tenner, A.J. Prevention of C5aR1 Signaling Delays Microglial Inflammatory Polarization, Favors Clearance Pathways and Suppresses Cognitive Loss, Mol. Neurodegeneration, 12:66, 2017. PMC5604420
Thielens, N.M., Tedesco, F., Bohlson,S.S., Gaboriaud,C., Tenner, A.J. C1q: A fresh look upon an old molecule. Mol. Immunol. 89 :73-83, 2017
Brubaker, W.D., Crane, A., Johansson, J.U., Yen, K., Garfinkel, K., Mastroeni,D, Leonard, B.,Asok, P., Bradt,B., Sabbagh,M., Wallace, T.L., Glavis-Bloom, C., Tenner, A.J., and Rogers,J., Peripheral complement interactions with amyloid ß peptide (Aß) in Alzheimer’s disease: 1. Erythrocyte clearance of Aß. Alzheimer’s and Dementia, 2017. PMID: 28475854 DOI:10.1016/j.jalz.2017.03.010
Hernandez, M.X., Namiranian,P., Nguyen, E., Fonseca, M.I., and Tenner, A.J. C5a increases the injury to primary neurons elicited by fibrillar amyloid beta. ASNeuro DOI: 10.1177/1759091416687871, 2017. PMID:28078911
Fonseca, M.I., Chu,S-H., Hernandez, M.X., Fang, M.J., Modarresi, L., Selvan, P., MacGregor G.R. and Tenner, A.J., Cell specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain J. Neuroinflammation, 14:48, 2017.
Fonseca, M.I., Chu,S-H., Pierce, A.L., Brubaker, W.D., Hauhart, R.E., Mastroeni, D., Clarke, E.V., Rogers, J., Atkinson, J.P., and Tenner, A.J., Analysis of the putative role of CR1 in Alzheimer’s disease: Genetic association, expression, and function. Plos One 11(2): e0149792 , 2016. (PMCID: PMC4767815)
Clarke, E.V., Weist, B.M., Walsh, C.M. and Tenner, A.J., Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic-cell mediated Th17 and Th1 T cell subset proliferation. J. Leuk. Biol. 97:147-160, 2015.
Clarke, E.V. and Tenner, A.J., Complement modulation of T cell immune responses during homeostasis and disease. J. Leuk. Biol. 96:745-756, 2014.
Benoit, M.E., Hernandez, M., Dinh, M., Benavente,F., Vasquez,O. and Tenner, A.J. C1q-induced LRP1B and GPR6, expressed early in AD mouse models, are essential for the C1q-mediated protection against Aß neurotoxicity, J. Biol. Chem. 288:654-665 2013. PMC3537064
Fonseca, M.I., McGuire, S.O., Counts,S.E. and Tenner, A.J., Complement Activation Fragment C5a Receptors, CD88 and C5L2, are associated with neurofibrillary pathology. J. Neuroinflammation 10:25, 2013. PMCID: PMC3605123
Chandrasekhar, A., Dinasarapu,D.R., Tenner, A.J., Subramaniam, S., Complement C1q subcomponent subunit A, UCSD Molecule Page, 2012, doi:10.6072/H0.MP.A004228.01)
Benoit, M.E., Clarke, E.V., Morgado, P., Fraser, D.A. and Tenner, A.J., Complement protein C1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells, J. Immunol 188 5682-5693, 2012.
Linnartz B, Kopatz J, Tenner AJ, Neumann H., Sialic Acid on the neuronal glycocalyx prevents complement c1 binding and complement receptor-3-mediated removal by microglia.
J Neurosci. 32(3):946-52, 2012.
Benoit ME, Tenner AJ., Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. J Neurosci. 2011 Mar 2;31(9):3459-69.
Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain.
Mol Immunol. 2011 Aug;48(14):1592-603.
Fonseca MI, Chu SH, Berci AM, Benoit ME, Peters DG, Kimura Y, Tenner AJ., Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease. J Neuroinflammation. 2011 Jan 15;8(1):4.
Fraser D.A., Tenner AJ., Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages. J Immunol. 2010 Oct 1;185(7):3932-9.
Fraser.D.A., Pisalyaput, K., and Tenner, A.J., C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J. Neurochem. 112:733-743, 2010.
Ager, R.R., Fonseca, M.I., Chu,S., Sanderson, S., Taylor, S.M., Woodruff, T.M., and Tenner, A.J., Microglial C5aR (CD88) expression correlates with amyloid-ß deposition in murine models of Alzheimer’s Disease, J. Neurochem. 113:389–401, 2010.
Klos, A., Tenner, A.J., Johswich, K-O., Ager, R.R., Reis, E.S. and J. Köhl, The Role of the Anaphylatoxins in Health and Disease. Mol. Immunol. 46:13624-13648, 2009.
Fonseca, M.F., Ager, R.R., Chu, S., Yazan, O., Sanderson, S., LaFerla, F.M., Taylor, S.M., Woodruff, T.M., Tenner, A.J., Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer Disease. J. Immunol. 183:1375-1383, 2009.
Fraser,D.A., Laust, A.K., Nelson, E.L. and Tenner, A.J., C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J.Immunol. 183;6175-6185, 2009
Zhou, J., Fonseca,, M.I., Pisalyaput, K. and Tenner, A.J. Complement C3 and C4 expression in murine mouse models of Alzheimer’s Disease. J. Neurochem. 106: 2080-2092, 2008.
Li,M., Ager, R.R., Fraser, D.A., Tjokro, N.O. and Tenner, AJ., Development of a Humanized C1q A Chain Knock-in Mouse: Assessment of Antibody Independent ß-Amyloid Induced Complement Activation. Mol. Immunol. 45:3244-3252, 2008.
Fraser, D.A. and Tenner, A.J. Directing an appropriate immune response: The role of defense collagens and other soluble pattern recognition molecules. Current Drug Targets, "Modulators of the Innate Immune System." Suzanne S. Bohlson, guest editor; Bentham Science Publishers, 9:113-122, 2008.
Pisalyaput, K. and Tenner, A.J., Complement component C1q inhibits ß-amyloid and serum amyloid P induced neurotoxicity via caspase and calpain-independent mechanisms. J. Neurochem. 104:696-707, 2008.
Lillis, A.P., Greenlee, M.C., Mikhailenko, I., Pizzo, S.V., Tenner, A.J., Strickland, D.K.and Bohlson, S.S. The low-density lipoprotein receptor-related protein (LRP/CD91) is not required for the C1q-triggered enhancement of phagocytosis in murine macrophages. J.Immunol. 181:364-373, 2008.
Tenner, A.J. and Pisalyaput, K., The Complement System in the CNS: Thinking again. In Central Nervous System Diseases and Inflammation, Eds: Thomas E. Lane, Monica Carson, Connie Bergmann, Tony Wyss-Coray, Springer, New York (Invited Review), pp. 153-174, 2008.
Fraser, D.A., Arora, M., Bohlson, S.S., Lozano, E., and Tenner, A.J., Generation of Inhibitory NFkB complexes and pCREB correlates with the anti-inflammatory activity of complement protein C1q in human monocytes. J. Biol. Chem. 282:7360-7367, 2007
Bohlson, S.S., Fraser, D.A., and Tenner, A.J. Complement Proteins C1q and MBL are Pattern Recognition Molecules that Signal Immediate and Long Term Protective Immune Functions. Mol. Immunol. 44:33-43, 2007.
Fraser, D.A., Bohlson, S.S., Jasinskiene, N., Rawal, N., Palmerini, G., Ruiz, S., Rochford, R., and Tenner, A.J., C1q and MBL, components of the innate immune system, influence monocyte cytokine expression, J. Leuk. Biol. 80:107-116, 2006.
Zhou, J., M. I. Fonseca, R. Kayed, S. D. Webster, I. Hernandez, O.Yazan, D. H. Cribbs, C.G. Glabe, and A. J. Tenner, “Novel Aß peptide immunogens modulate plaque pathology and inflammation in a murine model of Alzheimer’s Disease”, J. Neuroinflammation 2:28, 2005.
Bohlson, S.S., Silva, R., Fonseca, M. and Tenner, A.J. CD93 is rapidly shed from the surface of human myeloid cells and the soluble form is detected in human plasma, J. Immunol.175:1239-1247, 2005.
Fan, R. and Tenner, A.J. Differential regulation of Aß42-induced neuronal C1q synthesis and microglial activation. J. Neuroinflammation 2: 1-13, 2005
Bohlson, S.S., Zhang, M., Ortiz, C.E. and Tenner, A.J. The adaptor protein GIPC interacts with CD93 via a class I PDZ binding domain and a highly charged juxtamembrane region of the CD93 cytoplasmic tail. J. Leuk. Biol. 77: 80-89, 2005.
Fonseca, M.I., Zhou, J., Botto, M., and Tenner, A.J. Absence of Complement protein C1q leads to less neuropathology in transgenic mouse models of AD. ,J. Neuroscience 24: 6457-6465, 2004.
NIH NIA T32 AG000096 “Training in the Neurobiology of Aging” (MPI, C.W. Cotman, A.J. Tenner)
NIH NIA U54 AG054349
“UC Irvine AD Translational Center for Disease Model Resources” (MPI, A. J. Tenner, F M. LaFerla)
NIH NIA R01 AG060148 “Defining the Mechanistic Link between C5aR1 signaling and cognitive loss in Alzheimer's diseases.” (MPI, A.J. Tenner, A. Mortazavi)
NIH NIA R21 AG061746 “Modulating Polarization of Glial Cells in AD mouse models by a Complement Receptor Antagonist” (PI)
NIH R21 AG068573 (MPI R. Spitale, A.J. Tenner MPI) “Assessing cell specific proteomes in the presence and absence of C5a complement signaling in Alzheimer’s disease models”
American Association of Immunology
Society for Neuroscience
American Society for Cell Biology
International Complement Society, Founding Councilor
Society for Leukocyte Biology
American Society for Neurochemistry
American Society for Biochemistry and Molecular Biology
International Complement Society, Past President
ISTAART – Chair, PIA Immunity and Neurodegeneration
ADVANCE Equity Advisor
UCI MIND 2014—2016
International Complement Society 2014—2016
Associate Dean for Research
School of Biological Sciences 2007—2012
Cellular and Molecular Biosciences
Interdepartmental Neuroscience Program
UCI MIND - Institute for Memory Impairment and Neurological Disorders
Institute for Immunology