In Vivo Imaging of Microglia Responses to Blood-Brain Barrier Disruption
Katerina Akassoglou, Ph.D.
University of California, San Diego, La Jolla, CA
David Mahoney Neuroimaging Program
June 2007, for 3 years
Determining How Immune Cells in the Brain Create Damage When the Blood-Brain-Barrier is Disrupted
The researchers will use two-photon imaging in mice to determine whether blood factors that leak from disrupted blood vessels in the brain and induce immune cells residing in the brain to initiate damaging inflammation.
Brain function becomes impaired when blood vessels in the brain are disrupted and leak, as occurs in ischemic stroke (caused by blood vessel hemorrhage) or when the blood-brain-barrier is disrupted as occurs in spinal cord injury, multiple sclerosis (MS), Alzheimer’s disease, HIV encephalitis, bacterial meningitis, and brain tumors. Blood components leak inside the brain with subsequent hemorrhage, edema, and neuronal damage. Yet the molecular basis of how this vascular permeability impairs brain function is not known. The researchers suggest that blood factors that leak from damaged and permeable blood vessels in the brain induces early activation of immune microglial cells, which reside in the brain and mount an inflammatory response. The investigators’ earlier studies have shown that the blood factor fibrinogen, known for its coagulation properties, signals through the CD11b/CD18 integrin receptor to activate microglia. They will use two-photon cellular imaging in real time in mice to visualize microglial activation by blood-brain-barrier disruption.
Significance: Characterizing the molecular interface between the blood and brain in inflammatory damage associated with blood-brain-barrier disruption and vascular damage may lead to new therapeutic approaches to the numerous neurological conditions associated with this disruption.
Katerina Akassoglou, Ph.D.
Katerina Akassoglou, Ph.D., is an Assistant Professor at the Department of Pharmacology at the University of California, San Diego. Akassoglou performed her graduate studies at the University of Athens in Greece and the University of Vienna in Austria, where she developed a novel transgenic animal model for multiple sclerosis. As a recipient of the Human Frontier Science Program (HFSP) postdoctoral fellowship, Akassoglou performed her postdoctoral studies at SUNY at Stony Brook and the Rockefeller University. She continued her research at New York University with support from the Wadsworth Foundation and the National Multiple Sclerosis Society.
Her laboratory studies molecular mechanisms triggered by vascular damage to inhibit tissue repair. Her laboratory explored the hypothesis that blood leakage might not be merely a marker of vascular damage in neurologic disease, but an active participant in disease pathogenesis via the interaction of blood proteins with specific cellular receptors in the nervous system. Research in her laboratory identified fibrinogen as a signaling molecule in the nervous system that promotes inflammation and inhibits regeneration and proposed fibrinogen as a potential therapeutic target in multiple sclerosis.
Akassoglou has authored 29 peer-reviewed papers that have received more than 800 citations in scientific journals and textbooks and are featured in press releases worldwide. She has been an invited speaker at conferences and universities both nationally and internationally and has received six Young Investigator Awards. She is a member of the Expert Referee Panel of the Alzheimer’s Research Fund and an ad-hoc reviewer for several scientific journals. Akassoglou is the Director of the UCSD Pharmacology Summer Undergraduate Program and she currently mentors five postdoctoral fellows and one graduate student. Akassoglou is a named inventor on two US patents and in addition to the Dana Award in Brain and Immuno-imaging, she is the principal investigator of four research grants from the National Institute of Neurologic Diseases and Stroke (NIH/NINDS), the National Multiple Sclerosis Society and the Christopher Reeve Foundation.
Adams R.A., Bauer J., Flick M.J., Sikorski S.L., Nuriel T., Lassmann H., Degen J.L., and Akassoglou K. The fibrin-derived γ 377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med. 2007 Mar 19;204(3):571-82 .
Adams R.A., Passino M., Sachs B.D., Nuriel T., and Akassoglou K. Fibrin mechanisms and functions in nervous system pathology. Mol Interv. 2004 Jun;4(3):163-76 .
Akassoglou K., Adams R.A., Bauer J., Mercado P., Tseveleki V., Lassmann H., Probert L., and Strickland S. Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6698-703 .
Akassoglou K., Yu W.M., Akpinar P., and Strickland S. Fibrin inhibits peripheral nerve remyelination by regulating Schwann cell differentiation. Neuron. 2002 Mar 14;33(6):861-75 .
Schachtrup C., Lu P., Jones L.L., Lee J.K., Lu J., Sachs B.D., Zheng B., and Akassoglou K. Fibrinogen inhibits neurite outgrowth via β3 integrin-mediated phosphorylation of the EGF receptor. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11814-9 .