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Supporting Gladstone

Katerina AkassoglouKaterina Akassoglou, PhD
Associate Investigator
Gladstone Institute of Neurological Disease
University of California, San Francisco
Email: kakassoglou@gladstone.ucsf.edu
Telephone: 415-734-2512
Fax: 415-355-0824

Joint Appointments:
Associate Professor of Neurology
University of California, San Francisco
Associate Adjunct Professor of Pharmacology
University of California, San Diego


Areas of Investigation
Our lab studies mechanisms of neurovascular regulation of inflammation and tissue repair. Our current research focuses on identifying the molecular and cellular interface that blood proteins utilize to interact with nervous system cells and change their functions. Our ultimate goal is to target these interactions for therapeutic intervention in neurologic diseases.

figure
 Significance
Rupture of the vasculature allows the entry of blood proteins into the brain with subsequent edema formation and neuronal damage in a variety of neurologic diseases, such as stroke, multiple sclerosis (MS), Alzheimer's Disease (AD) and spinal cord injury. Our studies aim to unravel the molecular mechanisms of the CNS response to neurovascular changes with the ultimate goal to develop novel therapeutic strategies for neurologic diseases.

Approaches
We integrate animal modeling, histopathology, tissue culture and biochemistry techniques, as a multifaceted experimental approach to address the biological complexity of disease and repair mechanisms. We have developed in vivo imaging tools of the mouse brain and spinal cord that enable us to monitor disease processes in real time in the living animal.
Contributions
Our work showed that blood proteins are not merely markers of blood-brain barrier (BBB) disruption, but play a causative role in CNS disease by exerting both pro-inflammatory and neurodegenerative effects. Our studies identified fibrinogen as a potential novel target for therapeutic intervention in neuroinflammatory diseases and led to the design of inhibitory peptides that specifically inhibit the damaging proinflammatory effects of fibrinogen in the CNS without affecting its effects in blood coagulation. Our work also showed that removal of fibrin from the CNS via proteolytic degradation is regulated by the neurotrophin receptor p75NTR via a novel signaling pathway whereby p75NTR directly binds the phosphodieserase isoform PDE4A to compartmentalize cAMP signaling in cells. We also showed novel biological functions for p75NTR as a regulator of cell differentiation that is critical for the progression of fibrosis and tissue repair. Overall, our studies have suggested that bi-directional molecular mechanisms of communication between the blood and the brain determine the degree of damage and the regenerative potential of tissues within and outside of the nervous system.

Some questions addressed in ongoing studies

  • What is the functional role of BBB disruption in inflammation and neurodegeneration in neurologic diseases?
  • How does fibrinogen affect neuronal and glial functions?
  • Can the beneficial effect of fibrinogen inhibition be exploited therapeutically?
  • What are the biological functions of p75NTR?

Selected Recent Publications

  1. Le Moan N, Houslay DM, Christian F, Houslay MD, Akassoglou K. Oxygen-dependent cleavage of the p75 neurotrophin receptor triggers stabilization of HIF-1 alpha. Mol Cell, 2011, 44:476-90.
  2. Schachtrup C, Ryu JK, Helmrick MJ, Vagena E, Galanakis DK, Degen JL, Margolis RU, Akassoglou K. Fibrinogen triggers astrocyte scar formation by promoting availability of active TGFβ after vascular damage. J Neurosci, 2010, 30:5843-54.
  3. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG & Karin M. NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature, 2008, 453:807-11.
  4. Davalos D, Lee JK, Brinkman B, Zheng B, Akassoglou K. Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J Neurosci Methods, 2008, 169:1-7. Selected for Cover
  5. Schachtrup C, Lu P, Lee JK, Jones L, Sachs BD, Ju J, Zheng B, Akassoglou K. Fibrinogen inhibits neurite outgrowth via β3 integrin-mediated transactivation of the EGF receptor. Proc Natl Acad Sci USA, 2007, 104:11814-19.
  6. Sachs B.D., Baillie GS, McCall JR, Passino MA, Schachtrup C, Wallace DA, Dunlop AJ, MacKenzie KF, Klussmann E, Lynch MJ, Sikorski SL, Nuriel T, Tsigelny I, Zhang J, Houslay MD, Chao MV, Akassoglou K. p75 Neurotrophin Receptor Regulates Tissue Fibrosis through Inhibition of Plasminogen Activation via a PDE4/cAMP/PKA Pathway. J Cell Biol, 2007, 177:1119-32.
  7. Passino MA, Adams, RA, Sikorski SL, Akassoglou K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science, 2007, 315:1853-56
  8. Adams RA, Bauer J, Flick MJ, Sikorski SL, Nuriel T, Lassmann H, Degen JL, Akassoglou K. The fibrin-derived γ377-395 peptide inhibits microglia activation and reverses relapsing paralysis in central nervous system autoimmune disease. J Exp Med, 2007. 204:571-82. Selected for Cover
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