Katerina Akassoglou

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Katerina Akassoglou
Katerina Akassoglou, 2019 Barancik Prize Winner.jpg
Akassoglou in 2019
Born1972 (age 50–51)
Athens, Greece
NationalityGreek, American
Alma materUniversity of Athens, The Rockefeller University, New York University Skirball Institute of Biomolecular Medicine
Known forRole of fibrin in CNS inflammation and neurodegeneration
AwardsPresidential Early Career Award for Scientists and Engineers, John J. Abel Award in Pharmacology, Barancik Prize for Innovation in MS Research
Scientific career
FieldsNeuroimmunology, hematology
InstitutionsUniversity of California, San Francisco

Katerina Akassoglou is a neuroimmunologist who is a Senior Investigator and Director of In Vivo Imaging Research at the Gladstone Institutes. Akassoglou holds faculty positions as a Professor of Neurology at the University of California, San Francisco. Akassoglou has pioneered investigations of blood-brain barrier integrity and development of neurological diseases. She found that compromised blood-brain barrier integrity leads to fibrinogen leakage into the brain inducing neurodegeneration. Akassoglou is internationally recognized for her scientific discoveries.

Contents

Early life and education

Akassoglou was born in Athens, Greece. [1] She was inspired to pursue science in her undergraduate degree after her high school biology teacher assisted her in securing a summer internship in an Immunology lab. [2]

Akassoglou pursued her undergraduate degree at the University of Athens, graduating with a Bachelor of Science in biology in 1996. [1] She stayed at the University of Athens for her graduate degree, where she focused on neuroimmunology. [1] Her work explored the role of the cytokine TNFα in neuroinflammation under the mentorship of George Kollias and Lesley Probert within the Hellenic Pasteur Institute. [3] During her PhD, Akassoglou pursued training in neuropathology under the mentorship of Hans Lassman at the University of Vienna, Austria. [2] After completing her graduate studies in 1998, Akassoglou went to the United States to pursue her postdoctoral training under the mentorship of Sid Strickland at both the State University of New York at Stony Brook and the Rockefeller University. [2] She specialized in neurovascular biology and began to study the actions of Fibrin in the central nervous system. [4] She completed her postdoctoral training with Strickland in 2002 and then pursued a second postdoctoral fellowship at the New York University in the Skirball Institute of Biomolecular Medicine until 2003. [5]

Research

To explore the biology of Tumor Necrosis Factor signalling and probe its role in promoting disease, Akassoglou expressed TNFα in a transmembrane form on various brain cells. [6] She found that when she specifically expressed TNFα on astrocytes, this led to chronic inflammation and neurodegeneration. [6] This was not the case for TNFα expression on neurons, which highlighted that contact dependent TNF signals in the vicinity of astrocytes promote degeneration. Since it was evident that TNF signalling contributed to neurodegeneration, Akassoglou explored how TNF signalling in the central nervous system might be implicated in multiple sclerosis. [7] After inducing expressing of TNF from glial cells, she found oligodendrocyte death and myelin degeneration in the central nervous system, similar to the pathology one would find in MS. [7] Akassoglou then found that by blocking the TNFα receptor, she was able to abrogate inflammation and cell death suggesting a major role for TNF signalling in MS type brain pathology. [7] Early into her postdoctoral work, Akassoglou found that deposition of fibrin exacerbates neuronal injury and degeneration, and agents which lyse fibrinogen could act as potent therapeutic agents in neurodegeneration. [8] Akassoglou and her colleagues then probed the underlying mechanisms with which fibrin mediates neuronal damage, and they found that fibrin has an effect on Schwann Cell differentiation, keeping these cells in their non-myelinating state. [9] They further found that fibrin deposition also changes the extracellular matrix which inhibits Schwann Cell migration, further preventing re-myelination and leading to degeneration of peripheral nerves. [10]

Career

In 2004, Akassoglou joined the faculty in the Department of Pharmacology at the University of California, San Diego, where she is Adjunct Professor of Pharmacology. [11] Akassoglou's lab was centered around exploring neurovascular regulation of inflammation and tissue repair in the context of various neurological diseases. [12] Akassoglou's lab seeks to understand how blood proteins interact with cells and disrupt signalling in the brain parenchyma in times of blood-brain barrier disruption. [12] The overall goal of the lab is to target these mechanisms therapeutically in neurological disease to stop neurodegeneration and inflammation in the central nervous system. [12]

In 2008, Akassoglou accepted a position as an Associate Investigator at the Gladstone Institutes of Neurological Disease, maintaining an Adjunct Professorship in Pharmacology at UCSD. [2] Akassoglou is also a Professor of Neurology at the University of California, San Francisco Weill Institute for Neurosciences and she now Directs the Gladstone Center for In Vivo Imaging Research. [2] Her lab focuses on in vivo imaging to observe the behavior of immune and glial cells in the CNS during their interactions with blood proteins. [3]

Akassoglou's work has made changes to the way the field understands the interactions between the immune system, vascular system, and brain. [13] Her research elucidated the role that fibrin, a blood protein implicated in coagulation, has in the activation of microglia and the development of inflammation and neurodegeneration. [13] Akassoglou and her group developed immunotherapy to inhibit fibrin's actions in the brain to abrogate inflammation and prevent neuronal death. [13] Following this drug development, Akassoglou co-founded a spin-off company at Gladstone Institutes, called MedaRed, that will continue to develop neuroimmune targeting therapies for neurodegeneration treatment. Akassoglou is the first female investigator at Gladstone to have founded a spin-off company. [13]

Role of fibrinogen and microglial activation in neurodegeneration

Akassoglou and her team were the first to show that fibrinogen leakage into the brain parenchyma activates microglia and leads to neurodegeneration. [14] They found that when fibrinogen binds to the microglial receptor CD11b/CD18 it leads to microglial migration towards vasculature and the release of reactive oxygen species that damage neurons and lead to neuronal death. [14] However, when they blocked the receptor for fibrinogen on microglia, they no longer saw microglial migration towards vasculature and neuronal death did not occur. [14] They later found that fibrin binding to the microglial receptor directly promotes spine elimination of neurons and promotes cognitive decline. [15] Again, they used two-photon imaging to track the progress of disease and directly observe the role fibrinogen plays in microglial activation, spine elimination, and subsequent cognitive decline. [15]

In order to understand the progression towards neurodegeneration after blood brain barrier leakage, Akassoglou and her team tracked the activity patterns of thrombin and found that thrombin activity in the CNS preceded any sign of disease, and when thrombin activity peaked, so did fibrin activation of microglia, followed by neuron death. [16] These findings suggest that early detection of thrombin might be a suitable diagnostic for later neurodegeneration. [16]

Since Akassoglou and her team found fibrin so critical in the development of neurodegeneration in times of blood brain barrier leakage, they designed a novel therapeutic to target fibrin and prevent its effects on microglia. [17] They generated a monoclonal antibody, 5B8, that binds to fibrin and is able to inhibit CNS inflammation and oxidative stress without affecting blood clotting capabilities. [17] Akassoglou then proceeded to push this monoclonal antibody into the biotechnology space so that it can be further tested and eventually used in clinical trials and then for treatment of various types of neurodegenerative and brain autoimmune disorders. [17]

Awards and honors

Related Research Articles

<span class="mw-page-title-main">Glia</span> Support cells in the nervous system

Glia, also called glial cells(gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. The neuroglia make up more than one half the volume of neural tissue in our body. They maintain homeostasis, form myelin in the peripheral nervous system, and provide support and protection for neurons. In the central nervous system, glial cells include oligodendrocytes, astrocytes, ependymal cells, and microglia, and in the peripheral nervous system they include Schwann cells and satellite cells.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

<span class="mw-page-title-main">Microglia</span> Glial cell located throughout the brain and spinal cord

Microglia are a type of neuroglia located throughout the brain and spinal cord. Microglia account for about 10-15% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS). Microglia are distributed in large non-overlapping regions throughout the CNS. Microglia are key cells in overall brain maintenance—they are constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Since these processes must be efficient to prevent potentially fatal damage, microglia are extremely sensitive to even small pathological changes in the CNS. This sensitivity is achieved in part by the presence of unique potassium channels that respond to even small changes in extracellular potassium. Recent evidence shows that microglia are also key players in the sustainment of normal brain functions under healthy conditions. Microglia also constantly monitor neuronal functions through direct somatic contacts and exert neuroprotective effects when needed.

Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). EAE is also the prototype for T-cell-mediated autoimmune disease in general.

Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including the physiological functioning of the two systems in health and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

<span class="mw-page-title-main">Pathophysiology of multiple sclerosis</span>

Multiple sclerosis is an inflammatory demyelinating disease of the CNS in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage. The underlying cause is currently unknown. Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that MS is not a single disease but rather a spectrum.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury, toxic metabolites, or autoimmunity. In the central nervous system (CNS), including the brain and spinal cord, microglia are the resident innate immune cells that are activated in response to these cues. The CNS is typically an immunologically privileged site because peripheral immune cells are generally blocked by the blood–brain barrier (BBB), a specialized structure composed of astrocytes and endothelial cells. However, circulating peripheral immune cells may surpass a compromised BBB and encounter neurons and glial cells expressing major histocompatibility complex molecules, perpetuating the immune response. Although the response is initiated to protect the central nervous system from the infectious agent, the effect may be toxic and widespread inflammation as well as further migration of leukocytes through the blood–brain barrier.

Jaime Imitola is an American neuroscientist, neurologist and immunologist. Imitola’s clinical and research program focuses on Progressive Multiple Sclerosis and the molecular and cellular mechanisms of neurodegeneration and repair in humans. His research includes the translational neuroscience of neural stem cells into patients. Imitola is known for his discoveries on the intrinsic immunology of neural stem cells, the impact of inflammation in the endogenous neural stem cell in multiple sclerosis, and the ethical implications of stem cell tourism in neurological diseases.

<span class="mw-page-title-main">Pathophysiology of Parkinson's disease</span> Medical condition

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

Microglia are the primary immune cells of the central nervous system, similar to peripheral macrophages. They respond to pathogens and injury by changing morphology and migrating to the site of infection/injury, where they destroy pathogens and remove damaged cells.

<span class="mw-page-title-main">Urtė Neniškytė</span> Lithuanian neuroscientist (b. 1983)

Urtė Neniškytė is a Lithuanian neuroscientist. Her scientific interest and main area of work relates to the interaction of neurons and immune cells in the brain. She has studied the cellular mechanisms of Alzheimer's disease and is the co-author of the first articles about cell death in relation to phagocytosis.

<span class="mw-page-title-main">Robyn S. Klein</span> American neuroimmunologist

Robyn S. Klein is an American neuroimmunologist as well as the Vice Provost and Associate Dean for Graduate Education at Washington University in St. Louis Missouri. Klein is also a professor in the Departments of Medicine, Anatomy & Neurobiology, and Pathology & Immunology. Her research explores the pathogenesis of neuroinflammation in the central nervous system by probing how immune signalling molecules regulate blood brain barrier permeability. Klein is also a fervent advocate for gender equity in STEM, publishing mechanisms to improve gender equity in speakers at conferences, participating nationally on gender equity discussion panels, and through service as the president of the Academic Women’s Network at the Washington University School of Medicine.

<span class="mw-page-title-main">Bradlee Heckmann</span> American neuroimmunologist & pharmaceutical scientist

Bradlee L. Heckmann is an American biologist and pharmacologist who is the scientific co-founder and chief scientific officer of Asha Therapeutics, a biopharmaceutical company exploring novel therapeutics for neurological and oncological diseases. Heckmann holds academic appointments as a neuroimmunologist at the Byrd Alzheimer's Center and USF Health Neuroscience Institute and is assistant professor in molecular medicine at the USF Health Morsani College of Medicine. Heckmann's research has been focused on understanding the regulation of inflammatory and metabolic processes in the central nervous system, with particular emphasis on neurodegenerative diseases including Alzheimer's Disease and the role of the autophagy machinery in this setting.

Malú G. Tansey is an American Physiologist and Neuroscientist as well as the Director of the Center for Translational Research in Neurodegenerative Disease at the University of Florida. Tansey holds the titles of Evelyn F. and William L. McKnight Brain Investigator and Norman Fixel Institute for Neurological Diseases Investigator. As the principal investigator of the Tansey Lab, Tansey guides a research program centered around investigating the role of neuroimmune interactions in the development and progression of neurodegenerative and neuropsychiatric disease. Tansey's work is primarily focused on exploring the cellular and molecular basis of peripheral and central inflammation in the pathology of age-related neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis.

Li Gan is a neuroscientist and professor at Weill Cornell Medical College. She is known for her discovery of pathogenic tau protein acetylation in tauopathies and mechanisms of microglia dysfunction in neurodegeneration.

References

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  5. ↑ "Katerina Akassoglou | UCSF Profiles". profiles.ucsf.edu. Retrieved 2020-05-06.
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  8. ↑ Akassoglou, Katerina; Kombrinck, Keith W.; Degen, Jay L.; Strickland, Sidney (2000-05-29). "Tissue Plasminogen Activator–Mediated Fibrinolysis Protects against Axonal Degeneration and Demyelination after Sciatic Nerve Injury". Journal of Cell Biology. 149 (5): 1157–1166. doi:10.1083/jcb.149.5.1157. ISSN   0021-9525. PMC   2174825 . PMID   10831618.
  9. ↑ Akassoglou, Katerina; Yu, Wei-Ming; Akpinar, Pinar; Strickland, Sidney (2002-03-14). "Fibrin Inhibits Peripheral Nerve Remyelination by Regulating Schwann Cell Differentiation". Neuron. 33 (6): 861–875. doi: 10.1016/S0896-6273(02)00617-7 . ISSN   0896-6273. PMID   11906694.
  10. ↑ Akassoglou, Katerina; Akpinar, Pinar; Murray, Simon; Strickland, Sidney (2003-03-06). "Fibrin is a regulator of Schwann cell migration after sciatic nerve injury in mice". Neuroscience Letters. 338 (3): 185–188. doi:10.1016/S0304-3940(02)01387-3. ISSN   0304-3940. PMID   12581827. S2CID   2471133.
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  18. ↑ "ASPET | John J. Abel Award". www.aspet.org. Retrieved 2020-05-06.
  19. ↑ "Conrad N. Hilton Foundation Announces Recipients of the 2017 Marilyn Hilton Award for Innovation in Multiple Sclerosis Research". Hilton Foundation. Retrieved 2020-05-06.
  20. ↑ "Barancik Prize for MS Research Awarded to University of California Researcher". Barancik Foundation. 2019-03-06. Retrieved 2020-05-06.
  21. ↑ "Αυτές είναι οι Ελλήνίδες που τιμήθηκαν στα "Greek Top Women Awards"". www.parapolitika.gr (in Greek). 2019-03-08. Retrieved 2020-05-06.
  22. ↑ "Historic Fellows". American Association for the Advancement of Science.
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