Fibrinogen as a molecular mediator of cognitive dysfunction

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

DESCRIPTION (provided by applicant): The vascular system supplies the brain with oxygen and nutrients, providing trophic support to the nervous system(1) and enabling proper neuronal and cognitive function. In numerous neurological diseases where cognitive function is impaired, such as stroke,(3) Alzheimer's disease (AD),(4) and traumatic brain injury (TBI),(5) the function of the vascular system is perturbed. As a result of this cerebrovascular dysfunction, the delicate balance of the blood-brain barrier (BBB) is compromised and blood proteins leak into the brain.(6-10) Importantly, leakage of blood proteins into the brain often precedes neurodegeneration and cognitive decline.(3, 4, 6, 11, 12) Although blood-brain barrier disruption is a hallmark of cognitive pathologies, the molecular links between BBB disruption and cognitive dysfunction are unknown. The aim of my research is to elucidate the molecular link between cerebrovascular dysfunction and cognitive impairment. Fibrinogen, a critical component of blood coagulation, extravasates into the brain after vascular damage or BBB disruption.(2) My studies will focus on the role of fibrinogen in cognitive impairment. High plasma levels of fibrinogen are linked to the onset of demetia(13) and increase the risk of developing AD and vascular dementia.(14) Studies in animal models show that fibrinogen contributes to neurological disease by exacerbating inflammatory and neurodegenerative processes.(15-19) Indeed, genetic or pharmacologic depletion of fibrinogen protects against spatial memory deficits and neuroinflammation in AD mouse models.(19, 20) Though these studies demonstrate that fibrinogen is a major contributor to neurological dysfunction, the effects of fibrinogen on cognitive and behavioral impairment are not well understood. I hypothesize that fibrinogen leakage into the CNS leads to morphologic changes in neurons resulting in cognitive impairment. This hypothesis is supported by my preliminary data. I show that (1) fibrinogen is deposited in the brain after vascular damage due to TBI;(2) intracerebroventricular (i.c.v.) infusion of fibrinogen impairs memory recall and increases anxiety and depression in mice;(3) stereotactic cortical injection (s.c.i.) of fibrinogen decreases dendritic spine density in mice;and (4) cortical neurons treated with fibrinogen in vitro have thicker dendrites than controls. I propose to determine whether fibrinogen is necessary (Aim 1) or sufficient (Aim 2) to cause cognitive dysfunction and to examine the mechanism by which fibrinogen affects neuronal morphology (Aim 3). PUBLIC HEALTH RELEVANCE: Alzheimer's disease and vascular dementia are the leading causes of dementia and pose a major socioeconomic burden.(12) With 24.3 million people with dementia as of 2001 and a projected estimate of 81.1 million patients worldwide in 2040,(12) designing effective therapeutics that limit cerebrovascular dysfunction and cognitive decline is imperative. The identification of fibrinogen as a molecular mediator of cognitive dysfunction will establish the therapeutic potential of fibrinogen inhibitors to prevent cognitive dysfunction in the aging population.