Patients with central nervous system pathologies, including multiple sclerosis, stroke, spinal cord and traumatic injuries, often present with cognitive impairment, indicative of neuronal dysfunction. Although vascular damage and blood-brain barrier (BBB) disruption, which results in leakage of blood proteins into the brain parenchyma, are hallmarks of cognitive pathologies, the molecular links between BBB disruption and neuronal dysfunction remain poorly understtod. We have shown that CNS deposition of fibrinogen, a critical component of blood coagulation, is not merely a marker of BBB disruption, but plays a causative role in the regulation of inflammation and repair in the CNS by activating integrin receptors expressed in nervous system cells. Our long-term goal is to characterize the molecular pathways that are responsible for the effects of fibrinogen in nervous system pathogenesis, as a prerequisite for the development of therapeutic protocols that can specifically target the interactions between fibrinogen and its receptors and attenuate neuropathological disease processes. Our major hypothesis is that fibrinogen activates the CNS innate immune response to induce spine alterations and cognitive deficits in nervous system pathology. Our preliminary data demonstrate that a) stereotactic injection of fibrinogen into the dentate gyrus induces microglial activation and impairs memory recall, b) injection of fibrinogen induces neuronal loss, dendrite retraction and dendritic spine density reduction in mice as shown with in vivo two-photon microscopy, and c) genetic depletion of the CD11b/CD18 microglial receptor rescues fibrinogen-induced spine elimination and dendritic retraction.
Our specific aims are designed to test our working model, in which fibrinogen, deposited in the brain following BBB disruption and cerebrovascular abnormalities, activates the innate immune response and causes spine elimination and cognitive decline. We employ a cutting edge experimental design that includes in vivo two-photon imaging of neurons in transgenic mice expressing YFP under Thy1 promoter, following the dynamic interactions between microglial and spines over time in the living mouse, and pharmacologic and genetic inhibition of innate immune activation, including specific inhibition of fibrinogen interactions with CD11b that do not affects its beneficial functions in blood coagulation. Identifying the molecular interplay between fibrinogen following BBB disruption, activation of innate immunity, and neurotoxicity could potentially provide specific targets for pharmacological intervention in a variety of diseases characterized by cerebrovascular abnormalities or increased BBB permeability and cognitive impairment.

Public Health Relevance

BBB disruption is a hallmark of neuroimmune and neurodegenerative diseases, such as multiple sclerosis and stroke, but the molecular links between BBB disruption and cognitive dysfunction are unknown. Understanding the cross-talk between the vasculature and the brain is necessary to design effective therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082976-01A1
Application #
8715494
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2014-03-15
Project End
2016-02-29
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$286,500
Indirect Cost
$136,500
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158