Berislav V. Zlokovic is the director of the Zilkha Neurogenetic Institute and Professor and Chair of the Department of Physiology & Neuroscience at the Keck School of Medicine of USC, and a Professor of Biological Sciences at the Dornsife College of Letters, Arts and Sciences. Zlokovic studies the role of brain microcirculation, particularly the blood-brain barrier (BBB) in health and disease in the adult brain and during brain aging. He made major contributions to our understanding of the role of BBB in the pathogenesis and treatment of Alzheimer’s disease (AD) and stroke. Using animal models and studying human brain, his laboratory has shown that dysfunction in the BBB and brain microcirculation can accumulate before neuronal loss, and is an early biomarker of human cognitive dysfunction. His group showed that disrupted cross-talk between BBB-associated pericytes and brain capillary endothelial cells, and astrocytes and pericytes, within the neurovascular unit leads to neuronal dysfunction in both synapses and neurons, and that targeting the BBB cellular and molecular pathways can slow down, arrest and of prevent development of a neurodegenerative process. He has identified genes and receptors at the BBB that regulate brain levels of Alzheimer’s amyloid-beta toxin, which accumulates with aging and dementia. More recently, his team has developed new imaging techniques for studying BBB function in animal models and the living human brain. These findings contributed to development of Phase 2/3 clinical trials for AD patients. He co-discovered with J.H. Griffin vasculoprotective, neuroprotective, and anti-inflammatory activities of activated protein C (APC) in the CNS, including the receptor requirements and downstream signaling pathways. These findings have been translated in successfully completed Phase 2 trial of 3K3A-APC, a 2nd generation cytoprotective-selective APC analog, in ischemic stroke patients, which led to a Phase 3 efficacy and safety pivotal trial of 3K3A-APC in patients with ischemic stroke.
Current research interests
• We study humans at genetic risk for AD, and use transgenic models, and iPSC-based human models of the BBB and brain on a chip to understand how genes that carry risk for sporadic AD (e.g., APOE4, PICALM) affect the cerebrovascular system contributing to dementia, and AD disease onset and progression.
• We are developing cell and gene therapy approaches for AD using i) iPSC-derived human pericytes that express different protective target genes, and/or ii) BBB cell-specific gene delivery to influence neuronal and synaptic functions.
• We study APC biologics and mimetic peptides for white matter stroke, AD and ALS.
• We work on identifying small molecules that influence genes/pathways linked to AD.
• We work on CSF and imaging BBB biomarkers of human cognitive dysfunction.
• Recently, we have initiated studies to understand how gut microbiome influences BBB in relation to neuronal and synaptic functions using transgenic and human iPSC models.
• We initiated program on BBB molecular signatures (snRNAseq, proteome) in health and disease using transgenic and human models, and human brain tissue.
Zlokovic is recognized internationally as a leader in the fields of AD and stroke research. Thomson Reuters and Clarivate Analytics listed Zlokovic as one of “The World’s Most Influential Scientific Minds” for 18 consecutive years (2002-2020) for ranking in 1 % of the most-cited authors in the field of neurosciences and behavioral sciences. He received MetLife Award for Medical Research for “significant contributions to our understanding of Alzheimer’s disease and for bringing us closer to a cure”, Potamkin Prize from the American Academy of Neurology in recognition of outstanding achievements in research on Alzheimer’s and related neurodegenerative diseases”, Javits Award from NINDS in recognition of distinguished record of substantial contributions in a field of neurological sciences”, MERIT Award from NIA in recognition of sustained contribution to aging and leadership and commitment to the field”, and more recently USC Associates Award for Creativity in Research and Scholarship “the highest honor the university faculty bestows on its members for distinguished intellectual achievements” He is a fellow of the AAAS, The European Academy of Sciences, and The Dana Alliance for Brain Initiative. In 2017, 2018, 2019, 2020 and 2021, he was asked by the Nobel Assembly at Karolinska Institutet, The Nobel Committee to nominate candidates for the Nobel Prize in Physiology and Medicine. He is an active entrepreneur and inventor. He co-founded ZZ Biotech, a biotechnology company that is developing treatments for stroke and neurological disorders.
Featured Publications representing interests of the Zlokovic laboratory:
i-10 index: 259; h-index: 107; 51,753 citations (Google Scholar, Mar 2021); complete list in Google Scholar: https://goo.gl/2Npcj2
Nikolakopoulou AM, Wang Y, Ma Q, Sagare AP, Montagne A, Huuskonen MT, Rege SV, Dai Z, Körbelin J, Herz J, Zhao Z, Zlokovic BV. (2021) Endothelial LRP1 protects against neurodegeneration via cyclophilin A. Journal of Experimental Medicine 218(4):e20202207
Montagne A, Nation DA, Sagare AP, Barisano G, Sweeney MD, Chakhoyan A, Pachicano M, Joe E, Nelson AR, D’Orazio LM, Buennagel DP, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Reiman EM, Caselli RJ, Chui HC, Julia TCW, Chen Y, Pa J, Conti PS, Law M, Toga AW, Zlokovic BV. (2020) APOE4 leads to early blood-brain barrier dysfunction predicting human cognitive decline. Nature 581, 71-76.
Zhao Z, Zlokovic BV. (2020) Therapeutic TVs for crossing barriers in the brain. Cell 182(2):267-269.
Nation DA, Sweeney MD, Montagne A, Sagare AP, D’Orazio LM, Pachicano M, Sepehrband F, Nelson AR, Buennagel D, Liu CY, Harrington MG, Benzinger TLS, Fagan AM, Ringman JM, Schneider LS, Morris JC, Chui HC, Law M, Toga AW, Zlokovic BV (2019) Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature Medicine 25, 270-276.
Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Sagare AP, Lazic D, Sweeney MD, Kong P, Wang M, Owens NC, Lawson EJ, Xie X, Zhao Z, Zlokovic BV (2019) Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss. Nature Neuroscience 22, 1089–1098.
Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV (2019) Blood-Brain Barrier: From Physiology to Disease and Back. Physiological Reviews 99, 21-78.
Lazic D, Sagare AP, Nikolakopoulou AM, Griffin JH, Vassar R, Zlokovic BV (2019) 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice. Journal of Experimental Medicine 216(2), 279-293.
Lyden P, Pryor KE, Coffey CS, Cudkowicz M, …Davis TP, Toga AW, Griffin JH, Zlokovic BV, NeuroNEXT Clinical Trials Network NN104 Investigators. (2019) Final Results of the RHAPSODY Trial: A Multi-Center, Phase 2 Trial Using a Continual Reassessment Method to Determine the Safety and Tolerability of 3K3A-APC, A Recombinant Variant of Human Activated Protein C, in Combination with Tissue Plasminogen Activator, Mechanical Thrombectomy or both in Moderate to Severe Acute Ischemic Stroke. Annals of Neurology 85(1), 125-136.
Sweeney MD, Kisler K, Montagne A, Toga A, Zlokovic BV (2018) The role of brain vasculature in neurodegenerative disorders. Nature Neuroscience 21(10), 1318-1331
Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D, Barnes SR, Daianu M, Ramanathan A, Go A, Lawson EJ, Wang Y, Mack WJ, Thompson PM, Schneider JA, Varkey J, Langen R, Mullins E, Jacobs RE, Zlokovic BV (2018) Pericyte degeneration causes white matter dysfunction in the mouse CNS. Nature Medicine 24(3), 326-337.
Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer’s disease and other neurodegenerative disorders. Nature Reviews Neurology 14(3), 133-150.
Kisler K, Lazic D, Sweeney M, Plunkett S, Khatib ME, Vinogradov SA, Boas DA, Sakadzic S, Zlokovic BV (2018) Diverse protocols for in vivo measurements of cerebrovascular hemodynamic responses and tissue oxygen levels and delivery in the mouse brain. Nature Protocols 13(6), 1377-1402.
Sweeney MD, Zlokovic BV (2018) A lymphatic waste-disposal system implicated in Alzheimer’s disease. Nature 560 (7717) 172-174.
Kisler K, Nelson A, Montagne A, Zlokovic BV (2017) Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer’s disease. Nature Reviews Neuroscience 18, 419-434.
Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadžic S, Zlokovic BV (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nature Neuroscience 20, 406-416.
Wang Y, Zhao Z, Rege S, Griffin JH, Goldman SA, Zlokovic BV (2016) 3K3A-APC stimulates post-ischemic neuronal repair by human neural progenitor cells in mice. Nature Medicine 22 (9): 1050-1055.
Sweeney MD, Ayyadurai S, Zlokovic BV (2016) Pericytes of the neurovascular unit: key functions and signaling pathways. Nature Neuroscience 19 (6): 771-783.
Zhao Z, Nelson A, Betsholtz C, Zlokovic BV (2015) Establishment and dysfunction of blood-brain barrier. Cell 163, Nov 19;163(5):1064-78.
Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, Winkler EA, Ramanathan A, Kanekiyo T, Bu G, Owens NQ, Rege SV, Si G, Ahuja A, Zhu D, Miller CA, Schneider JA, Maeda M, Maeda T, Sugawara T, Ichida JK, Zlokovic BV (2015) Central role for PICALM in amyloid-? blood-brain barrier transcytosis and clearance. Nature Neuroscience 18, 978-987.
Winkler EA, Nishida Y, Sagare AP, Rege SV, Bell RD, Perlmutter D, Sengillo JD, Hillman S, Kong P, Nelson AR, Sullivan JS, Zhao Z, Meiselman HJ, Wendy RB, Soto J, Abel ED, Makshanoff J, Zuniga E, De Vivo DC, Zlokovic BV (2015) GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nature Neuroscience 18, 521-530.
Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, Toga AW, Jacobs RE, Liu CY, Amezcua L, Harrington MG, Chui HC, Law M, Zlokovic BV (2015) Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296-302.
Griffin JH, Zlokovic BV, Mosnier LO (2015) Activated Protein C: Biased for Translation. Blood 125 (19), 2898-2907.
Zhao Z and Zlokovic BV (2014) Blood-Brain Barrier: A Dual Life of MFSD2A? Neuron 82, 728–730.
Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, Wang Y, Zhong G, Sullivan JS, Griffin JH, Cleveland DW, Zlokovic BV (2014) Blood-spinal cord barrier disruption contributes to early motor neuron degeneration in ALS model mice. Proceedings of the National Academy of Sciences USA 111(11), E1035-42.
Bell RD, Winkler E, Sagare A, Singh I, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk B, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512-516.
Deane R, Singh I, Sagare A, Bell R, Ross NT, Larue B, Love R, Perry S, Deane RJ, Thiyagarajan M, Zarcone T, Friedman A, Miller BL, Zlokovic BV (2012) A novel multi-modal RAGE-specific inhibitor controls amyloid-beta-mediated brain disorder in mice. Journal of Clinical Investigation 122 (4), 1377-1392.
Winkler E, Bell R, Zlokovic BV (2011) Functions of CNS pericytes in health and disease. Nature Neuroscience 14, 1398-1405.
Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nature Reviews Neuroscience 12, 723-738.
Winkler EA, Bell RD, Zlokovic BV (2011) Lack of Smad and Notch Leads to a Fatal Game of Brain Pericyte Hopscotch. Developmental Cell (Cell) 20 (3), 279-281.
Zlokovic BV, Griffin JH (2011) Activated protein C cytoprotective pathways and implications for stroke and neurological disorders. Trends in Neurosciences 34 (4), 1198-2009.
Zlokovic BV (2010) Neurodegeneration and the neurovascular unit. Nature Medicine 16(12), 1370-71.
Bell RD, Winkler EA, Sagare A, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and the neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409-427.
Zhu D, Wang Y, Singh I, Bell RD, Deane R, Zhong Z, Sagare A, Winkler EA, Zlokovic BV (2010) Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor. Blood 115, 4963-4972.
Bell RD , Deane R, Chow N, Long X, Sagare A, Singh I, Streb JW, Guo H, Rubio A, Van Nostrand W, Miano JP, Zlokovic BV (2009) SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nature Cell Biology 11(2), 143-153.
Zhong Z, Ilieva H, Hallagan L, Bell R, Singh I, Paquette N, Thiyagarajan M, Deane R, Fernandez JA, Lane S, Zlokovic AB, Liu T, Griffin JH, Chow N, Castellino F, Stojanovic K, Cleveland DW, Zlokovic BV (2009) Activated protein C slows ALS-like disease by transcrptionally inhibiting SOD1 in motor neurons and microglial cells. Journal of Clinical Investigation 119(11), 3437-3440.
Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) Apolipoprotein E isoform-specific disruption of Alzheimer’s amyloid ?-peptide clearance from mouse brain. Journal of Clinical Investigation 118(12), 4002-4013.
Zhong Z, Deane R, Zarina A, Parisi M, Shapovalov Y, 0’Banion K, Stojanovic K, Sagare A, Boillee S, Cleveland DW, Zlokovic BV (2008) ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nature Neuroscience 11(4), 420-422.
Zlokovic BV (2008) Blood-brain barrier in health and chronic neurodegenerative disorders. Neuron, 57, 178-201.
Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Pelmutter D, Coma M, Zhong Z, Zlokovic BV (2007) Clearance of amyloid-beta by circulating lipoprotein receptors. Nature Medicine 13 (9), 1029-1031.
Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A, Van Nostrand W, Miano JM, Zlokovic BV (2007). Serum response factor and myocardin mediate cerebral arterial hypercontractility and blood flow dysregulation in Alzheimer’s phenotype. Proceedings of the National Academy of Sciences USA 104, 823-828.
Mosnier L, Zlokovic BV, Griffin JH (2007) The cellular protein C pathway. Blood 109(8), 161-172.
Cheng T, Petraglia A, Li Z, Meedakshisudaram T, Wu Z, Zhong Z, Liu D, Maggirwar SB, Deane R, Fernandez J, LaRue B, Griffin J, Chopp M, Zlokovic BV (2006) Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nature Medicine 12 (11), 1278-1285.
Zlokovic BV (2006) Remodeling after stroke. Nature Medicine 12 (4) 390-391.
Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, Brooks A, Kanagala S, Rubio A, Sagare A, Liu D, Li F, Armstrong D, Gasiewicz T, Zidovetski R, Song H, Hofman F, Zlokovic BV (2005) Role of MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nature Medicine 11(9), 959-965.
Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends in Neurosciences 28, 202-208.
Deane R, Wu Z, Davis J, Yan SD, Hamm K, Sagare A, Xu F, Spijkers P, Lenting PJ, Van Nostrand WE, Zlokovic BV (2004) LRP-amyloid-beta interaction mediates differential brain efflux of Abeta isoforms. Neuron 43, 33-44.
Liu D, Cheng T, Guo H, Fernandez AJ, Griffin JH, Song X, Zlokovic BV (2004) Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nature Medicine 10, (12), 1379-1383.
Guo H, Liu D, Gelbard H, Cheng T, Fernandez JA, Insalaca R, Griffin JH, Zlokovic BV (2004) Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41, 563-572.
Deane R, Yan SD, Kumar R, Jovanovic S, LaRue B, Welch D, Maness L, Yu J, Zhu H, Ghiso J, Frangione B, Schmidt AM, Arnold B, Liliensiek B, Nawroth P, Hofman F, Kindy M, Stern D, Zlokovic BV (2003) RAGE mediates amyloid-ß peptide transport across the blood-brain barrier and accumulation in brain. Nature Medicine 9(7), 907-913.
Cheng T, Liu D, Fernández JA, Griffin JH, Castellino F, Rosen E, Fukudome K, Zlokovic BV (2003) Activated protein C blocks P53-mediated apoptosis in ischemic human brain endothelium and is neuroportective. Nature Medicine 9, 338-342.
Domotor E, Benzakour O, Griffin JH, Yule D, Fukudome K, Zlokovic BV (2003) Activated protein C alters cytosolic Ca2+ flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease-activated receptor-1. Blood 101, 4797-4801.
Shibata M, Subramanyan RK, Amar A, Fernandez J, Griffin J, Zlokovic BV (2001) Anti-inflammatory, antithrombotic and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke with cerebrovascular thrombosis. Circulation 103, 1799-1805.
Shibata M, Yamada S, Kumar RS, Calero M, Bading B, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV (2000) Clearance of Alzheimer’s amyloid-ß1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. Journal of Clinical Investigation 106(12), 1489-1499.
Zlokovic BV, Shinya Y, Holtzman D, Ghiso J, Frangione B (2000) Clearance of amyloid ß-peptide from brain: transport or metabolism? Nature Medicine 6, 718-719.
Mackic JB, Stins M, McComb JG, Calero M, Ghiso J, Kim KS, Yan SD, Stern D, Schmidt AM, Frangione B, Zlokovic BV (1998) Human blood-brain barrier receptors for Alzheimer's amyloid-? 1-40: Asymmetrical binding, endocytosis and transcytosis at the apical side of brain microvascular endothelial cell monolayer. Journal of Clinical Investigation 102, 734-743.
Zlokovic BV, Martel CL, Matsubara E, McComb JG, Zheng G, McCluskey RT, Frangione B, Ghiso J (1996) Glycoprotein 330/megalin: Porbable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer's Disease amyloid-? at the blood-brain and blood-cerebrospinal fluid barriers. Proceedings of the National Academy of Sciences USA 93, 4229-4236.