Director's Page

Zlokovic

Berislav Zlokovic, MD, PhD

Dean's Professor
Director, Center for Neurodegenerative & Vascular Brain Disorders
Director, Interdisciplinary Program in Dementia Research

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

 

RESEARCH TOPICS

  • Alzheimer's Disease
  • Ischemia and Stroke
  • Activated Protein C System
  • Amytrophic lateral sclerosis
  • Blood-Brain Barrier

 

Research Overview

In our laboratory we study how damage to brain microcirculation and defective blood-brain barrier (BBB) function contribute to neuronal dysfunction in Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Using different transgenic mouse lines we study the neural consequences of BBB dysfunction/breakdown, hypoperfusion and hypoxia at the molecular and cellular levels. Our studies focus on disrupted cell-to-cell signaling within the neurovascular unit such as (i) platelet-derived growth factor receptor β deficiency causing pericyte degeneration, BBB breakdown and hypoperfusion preceding neurodegeneration; (ii) regulation of key neurovascular functions by apolipoprotein E (apoE) genotype and astrocyte-secreted apoE; (iii) how alterations in the expression of the vascular-specific genes discovered through genome-wide transcriptional profiling of brain endothelium and other vascular cells in AD lead to aberrant brain angiogenesis, vascular regression, blood flow reductions and faulty amyloid-beta clearance; and (iv) the role of microhemorrhages in ALS. Therapeutically, we focus on vascular-mediated amyloid-beta transport across the BBB via LRP1 and RAGE, soluble LRP1 and RAGE blockers in AD models as well as individuals with mild cognitive impairment and AD. A therapy based on this novel approach is currently being translated to humans. Next, we study the roles of apoE2, apoE3, apoE4 and apoJ in amyloid-beta clearance via lipoprotein receptors at the BBB and by astrocytes. Beyond the work in AD, we study activated protein C (APC) signaling in different cell types of the neurovascular unit in rodent models of stroke and ALS. These studies focus on BBB integrity, neuroinflammatory response, neuronal protection, neural plasticity, angiogenesis, neurogenesis and stem cells. Based on this work, APC treatment is currently being translated to stroke patients. The laboratory presently holds research grants from the National Institutes of Health (NIH) and the ALS Association.

 

 

Selected Publications

Alzheimer’s and Neurodegenerative Disorders

Winkler E, Bell R, Zlokovic BV (2011) Functions of CNS pericytes in health and disease Nature Neuroscience (in press)

Zlokovic BV (2010) Neurodegeneration: are we overlooking the role of 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.

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, 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, 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 Alzheimer’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 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 Medicine 11(9), 959-965.

Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer’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-β 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 Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier J Clin Invest 106(12), 1489-1499.

 

Activated Protein C Pathway in Brain

Zlokovic BV, Griffin JH (2011) Activated protein C cytoprotective pathways and implications for stroke and neurological disorders Trends Neurosci 34 (4), 1198-2009.

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, 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.

 

Education

  • M.D., Medical Board of California (LicenseA053853)
  • Postdoctoral fellow, King’s College University of London
  • Postdoctoral fellow, St. Thomas’s Hospital University of London
  • M.D. Ph.D., School of Medicine, University of Belgrade