Berislav V. Zlokovic
Director, Zilkha Neurogenetic Institute
Professor and Chair,
Department of Physiology & Biophysics
Director, Center for Neurodegeneration & Regeneration
Zilkha Neurogenetic Institute
Keck School of Medicine of USC
- Alzheimer's Disease
- Ischemia and Stroke
- Activated Protein C System
- Amytrophic lateral sclerosis Blood-Brain Barrier
Research OverviewIn my laboratory we have a long standing interest in understanding the role of cerebral blood vessels and blood-brain barrier (BBB) in pathogenesis of neurodegenerative disorders such as Alzheimer’s disease (AD) and more recently amytrophic lateral sclerosis (ALS), as foundations for development of new therapies for AD and related neurodegenerative disorders as well as stroke. My research team is working on the cellular and molecular mechanisms in blood vessels and the neurovascular unit causing BBB disruption which leads to neuronal dysfunction and degenerative changes using models of AD and pericyte-deficient rodents as well as analysis of human brain. Our discoveries contributed to the development of clinical trials based on amyloid-beta clearance in AD patients, and a new therapeutic approach for stroke based on activated protein C mutant which has been initiated in August 2012.
Alzheimer's and Neurodegenerative Disorders
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-b-mediated brain disorder in mice J 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 Alzheimerâ€™s disease and other disorders Nature Reviews Neuroscience 12, 723-738.
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.
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-b clearance in brain vascular cells Nature Cell Biol 11(2), 143-153.
Zhong Z, Deane R, Zarina A, Parisi M, Shapovalov Y, 0â€™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, 420-422.
Zlokovic BV (2008) Blood-brain barrier in health and chronic neurodegenerative disorders Neuron 57, 178-201.
Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV (2008) Apolipoprotein E isoform-specific disruption of Alzheimerâ€™s amyloid b-peptide clearance from mouse brain J Clin Invest 118(12), 4002-4013.
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-b 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 Alzheimerâ€™s phenotype. Proc Natl Acad Sci 104, 823-828.
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 Alzheimerâ€™s neurodegeneration Trends Neurosci 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-b interaction mediates differential brain efflux of Ab isoforms Neuron 43, 33-44.
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-Î˛ peptide transport across the blood-brain barrier and accumulation in brain Nature Medicine 9(7), 907-913.
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 Alzheimerâ€™s amyloid-Î˛1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier J Clin Invest 106(12), 1489-1499.
Zlokovic BV, Griffin JH (2011) Activated protein C cytoprotective pathways and implications for stroke and neurological disorders Trends Neurosci 34 (4), 1198-2009.
Activated Protein C in the Nervous System
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 J Clin Invest 119(11), 3437-3440.
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.
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.
Cheng T, Liu D, FernĂˇndez 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.