Blood-brain barrier (BBB) disruption is a pathological hallmark of many neurological diseases, including stroke, multiple sclerosis (MS), Alzheimer?s disease (AD), and traumatic brain injury (TBI). Compromise of BBB integrity results in leakage of blood proteins into the brain parenchyma. Leakage of blood proteins into the brain may precede neurodegeneration and cognitive decline, but the molecular link between vascular damage and neurodegeneration is unknown. Fibrinogen, a critical component of blood coagulation, extravasates into the brain after vascular damage or BBB disruption. In humans, elevated plasma fibrinogen is a risk factor for cognitive impairment, and fibrinogen has been detected in the brains of patients with MS, schizophrenia, HIV- encephalopathy, ischemia, AD, and normal aging. Studies in animal models show that fibrinogen contributes to neurological disease by exacerbating inflammatory and neurodegenerative processes. Indeed, genetic or pharmacologic depletion of fibrinogen reduces neuroinflammation and reverses paralysis in MS models and protects against neuroinflammation and cognitive dysfunction in AD models. These studies suggest that fibrinogen is a major contributor to neurological dysfunction, however, the precise effects of fibrinogen on neuronal functions are not yet well understood. My long-term objective is to identify the molecular pathways mediating the effects of fibrinogen on disease pathogenesis as an essential step toward the development of therapeutic strategies that specifically target the damaging functions of fibrinogen in the CNS without affecting its beneficial effects in blood coagulation. My major hypothesis is that fibrinogen leakage drives neuronal dysfunction and cognitive impairment via activation of the CNS innate immune response. This hypothesis is supported by preliminary data showing that (1) stereotactic injection of fibrinogen into the dentate gyrus induces microglia activation and cognitive impairment; (2) fibrinogen induces dendrite retraction and spine elimination, as shown by in vivo 2-photon (2P) microscopy; (3) genetic depletion of the CD11b/CD18 microglial receptor prevents fibrinogen-induced spine elimination and dendritic retraction; (4) BBB disruption by controlled cortical impact results in massive parenchymal deposition of fibrinogen; and (5) Fibrinogen depletion or genetic inhibition of fibrinogen binding to the microglial CD11b/CD18 receptor reduces cortical damage after CCI. I propose to determine whether fibrinogen is necessary for cognitive deficits in a model of TBI (Aim 1), investigate the in vivo effects of fibrinogen on neuronal dysfunction (Aim 2), and determine the mechanisms by which fibrinogen induces neuronal dysfunction (Aim 3).

Public Health Relevance

The integrity of the brain?s vasculature is compromised in many neurological disorders, including Alzheimer?s disease, stroke, multiple sclerosis, and traumatic brain injury, and often occurs early in disease. When the vasculature becomes damaged in such conditions, a circulating blood protein called fibrinogen leaks into the brain where it has deleterious consequences for brain cells. My studies will elucidate how fibrinogen impacts cognitive function and will identify potential strategies for targeting fibrinogen?s negative actions to reduce cognitive impairment in neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS096920-02
Application #
9495575
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bellgowan, Patrick S F
Project Start
2016-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Ryu, Jae Kyu; Rafalski, Victoria A; Meyer-Franke, Anke et al. (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol 19:1212-1223
Akassoglou, Katerina; Merlini, Mario; Rafalski, Victoria A et al. (2017) In Vivo Imaging of CNS Injury and Disease. J Neurosci 37:10808-10816
Bardehle, Sophia; Rafalski, Victoria; Akassoglou, Katerina (2016) Finding the 'ubiquitous' threads in infection and autoimmune neuroinflammation. Nat Immunol 18:7-8