Email this pageDirector's Page
Berislav Zlokovic, MD, PhD
Dean's Professor
Professor of Neurosurgery and Neurology
Director, Center for Neurodegenerative & Vascular Brain Disorders
Contact Information:
Center for Neurodegenerative and Vascular Brain Disorders
Arthur Kornberg Medical Research Building
University of Rochester
601 Elmwood Avenue, Box 670
Rochester, NY 14642
Phone: (585)273-3132 Fax: (585)273-3133
e-mail: Berislav_Zlokovic@urmc.rochester.edu
Faculty Rank:
Professor of Neurosurgery and Neurology
Dean's Professor
Director, Center for Neurodegenerative and Vascular Brain Disorders
Medical School:
University of Belgrade
Graduate School:
Queen Elizabeth College, London
PostDoctoral Fellowships:
King's College, University of London
Special Interests:
Neurobiology of Alzheimer's Disease and Treatments
Brain Ischemia Mechanisms and Neuroprotecive Mechanisms
Blood-Brain Barrier Transport and Molecular Biology
Berislav V. Zlokovic, M.D. Ph.D. is Dean's Professor and Professor of Neurosurgery & Neurology, and Director, Center for Neurodegenerative and Vascular Brain Disorders at the University of Rochester. Dr. Zlokovic directs NIH-funded Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research at the University. He is Scientific Director and Co-Founder of Socratech L.L.C., ZZ Biotech and ZZ Alztech biotechnology companies with a mission to develop new therapies for the aging and damaged brain, including those affected by stroke, Alzheimer’s disease (AD) and other neurodegenerative disorders.
Much of the work by Dr. Zlokovic, who is known internationally for his work on stroke as well as Alzheimer’s, focuses on the crucial role of blood vessels. He has shown that blood circulation plays a key role in ridding the brain of the toxic amyloid beta that attacks the brains of Alzheimer’s patients. For the last five years, Dr. Zlokovic has focused his attention on molecular and cellular mechanisms mediating transport of amyloid beta-protein between blood and brain across the blood-brain barrier and its clearance from brain. His research has identified the blood-brain barrier transport receptors LRP and RAGE which control the amount of amyloid beta-peptide neurotoxin in the brain at any time. He suggested that AD may develop as a clearance storage disorder with the resulting neurodegeneration. He suspected that the accumulation of amyloid-beta in the brain might have to do with an abnormality in a patient's ability to clear the protein through the membranes that controls the passage of substances to and from the central nervous system. Based on his discoveries, Dr. Zlokovic’s group and other groups are currently working on development of new anti-Ab clearance therapies to prevent amyloid-beta accumulation in brain and promote its clearance. An important translational extension of Dr. Zlokovic’s work on Alzheimer’s clearance hypothesis is recently funded safety and efficacy multicenter clinical trial with RAGE/amyloid-beta inhibitors in mild-to-moderate AD patients sponsored by the ADCS NIA.
Dr. Zlokovic also pioneered studies on vascular-specific genes in AD. His team discovered that low expression of vascular-restricted mesenchyme homeobox gene 2 in brain endothelium of the blood-brain barrier in AD individuals results in aberrant formation of new blood vessels and faulty clearance of amyloid-beta. The group recently reported that increased expression of serum response factor and myocardin in brain vascular smooth cells in AD is responsible for hypercontractility of small cerebral arteries and diminished cerebral hyperemia after brain activation which contributes to the development of cerebral amyloid angiopathy. These exciting findings have led to insights regarding potential new avenues for treatment of Alzheimer's patients and the development of new drug discovery programs through library screening of chemically diverse small molecules.
Dr. Zlokovic has also made significant contributions to the field of neuroprotection and ischemic injury. His laboratory discovered much of the cellular and molecular pathways in injured neurons and cerebral vascular endothelium which mediate protection of the nervous system by a serine protease activated protein C (APC). Prior to Zlokovic’s work in the central nervous system, APC was known mainly as an anticoagulant and anti-inflammatory circulating blood factor. Zlokovic’s team reported on important role of protein C pathway in brain and demonstrated that endothelial protein C receptor-dependent activation of protease activated receptor-1 by APC prevents p53-dependent and caspase-3-dependent apoptotic signaling in stressed brain endothelium in vitro, and is neuroprotective in vivo. The group next showed that blood-derived APC has direct neuronal protective activity against divergent inducers of neuronal apoptosis. His team demonstrated that APC blocks both the intrinsic and the extrinsic apoptotic pathways in models of neuronal injury in vitro and in vivo. Recently the group showed that APC activates an anti-hemorrhagic pathway in ischemic brain endothelium by blocking nuclear factor kappa-B-dependent upregulation of matrix metalloproteinase-9. An important translational extension of Dr. Zlokovic’s work on protein C is recently funded multicenter clinical trial with APC for stroke.
Recently, the Zlokovic laboratories extended their interest in APC-based treatments to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), AD, Parkinson’s Disease (PD), as well as to acute brain injury. Zlokovic has also initiated recently new exciting cellular, molecular and system studies to understand the role of the protein S system in brain.
The Zlokovic laboratories saw continued growth and now include 6 fulltime faculty members and 19 staff members including 1 senior associate/lab manager, 4 postdoctoral fellows, 5 technicians, 2 graduate students, 4 medical students and 3 undergraduates working on projects during 2007-2008. The lab continues to be a popular choice of destination for students looking to engage in cutting edge neuroscience research. With his major research emphasis revolving around research in Alzheimer’s and stroke, and more recently ALS, Dr. Zlokovic has accounted for over 40 publications over past 3 years of which one third was in high impact general journals such as Nature Medicine, Neuron, Nature Neuroscience, Journal of Clinical Investigation and Proceedings of the National Academy of Sciences.
Zlokovic was born in Belgrade in 1952. He received his M.D./Ph.D. from the University of Belgrade. He received post-doctoral training in Transport Biology at the Queen Elizabeth College London and in Neurobiology at the King’s College London with the renowned British scientist Dr. Hugh Davson who was know best for his work on Davson-Danielli cell membrane model. From 1983 to 1993, Zlokovic published several papers that have influenced current thinking on the role of the blood-brain barrier in health and disease, particularly discovery of receptor-mediated peptidergic transport systems for neuroactive peptides at the blood-brain barrier. From 1989 to 2000, Zlokovic was Professor of Neurosurgery & Physiology at the University of Southern California. In 1991, he met Dr. Blas Frangione and developed an interest to study Alzheimer’ disease. Dr. Zlokovic co-founded with Mr. Selim K. Zilkha in 2000 a program on “Gene Discovery in Alzheimer’s Neurovasculature” that has been carried out in Socratech Research Laboratories. The group has first identified vascular-specific genes in AD, and next small molecule candidates which regulate interactions between vascular genes in small cerebral arteries. Socratech is currently developing a new class of drugs to control the development of cerebral amyloid angiopathy which is a common pathological feature in AD. Zilkha and Zlokovic co-funded in 2006 and 2007 two new biotechnology programs on manufacturing the second generation APC for stroke, ALS, AD, multiple sclerosis, other neurodegenerative disorders and sepsis (ZZ Biotech) and soluble lipoprotein receptors for AD (ZZ Alztech). Dr. Zlokovic has served on and chaired numerous government and non-profit advisory boards and has over 250 publications.
His accomplishments have earned him a MERIT Award from the National Institute on Aging, awards from the National Institute on Neurological Disorders and Stroke and National Heart Lung and Blood Institute, Award from the National Institute on Aging to direct a multi-institutional program in “The Aging Brain: Cerebrovascular Mechanisms and amyloid-beta”, and one of the inaugural ISOA/Elan awards for his work on novel approaches to drug discovery for Alzheimer’s disease. Dr. Zlokovic was the 2006 winner of the prestigious Metropolitan Life Foundation Award for Medical Research which is given to neuroscientists who made significant contributions to our understanding of Alzheimer’s disease and who bring us closer to a cure. He received in 2007 the Javits Award for his distinguished record of substantial contributions in a field of neurological science.
In his spare time, Dr. Zlokovic enjoys swimming and tennis. He continues to sing from a repertoire of opera classics; and loves relaxing with his wife Zora, an internationally acclaimed concert pianist, and daughter Anna.
Key Publications last 4 years
NEUROBIOLOGY OF ALZHEIMER’S DISEASE AND TREATMENTS
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 Med, 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. 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 Med 11(9), 959-965.
Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’s neurodegeneration Trends Nsci 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 A-beta 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-β peptide transport across the blood-brain barrier and accumulation in brain Nature Med 9(7), 907-913.
BRAIN ISCHEMIA MECHANISMS AND NEUROPROTECTION MECHANISMS
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 Med 12 (11), 1278-1285.
Zlokovic BV (2006) Remodeling after stroke Nature Med 12 (4) 390-391.
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 Med 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, 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 Med 9, 338-342.
BLOOD-BRAIN BARRIER AND VASCULAR CHANGES IN CHRONIC NEURODEGENERATIVE DISORDERS
Zlokovic BV (2008) Blood-brain barrier in health and chronic neurodegenerative disorders, Neuron, 57, 178-201.
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 Neurosci 11, 420-422.