Roskamp Institute scientist and Open University PhD students presented posters during VA Research Day, at James A. Haley Veterans’ Hospital, on April 14th 2011. You can find the abstracts of these poster below.
Proteomic-based identification of a CNS biological profile of delayed cognitive impairment in mice exposed to Gulf War agents.
Laila Abdullah,* Alex Bishop,* John Phillips, Scott Ferguson,*†‡ Benoit Mouzon,*†‡*‡ Jon Reed,*† Gogce Crynen,*‡ Myles Mullan,*† Venkat Mathura,* Michael Mullan,*†
Ghania Ait-Ghezala,*†‡ and Fiona Crawford*†‡
*Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243
†James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL, 33612
‡The Open University, Walton Hall, Milton Keynes, MK7 6AA
Background: Gulf War Illness (GWI) is a chronic multisymptom condition with a central nervous system (CNS) component, for which there is no treatment currently available. It is now believed that the combined exposure to Gulf War (GW) agents, including pyridostigmine bromide (PB) and pesticides, such as permethrin (PER), was a key contributor to the etiology of GWI. Aim: In this study, a proteomic approach was used to characterize the biomolecular disturbances that accompany neurobehavioral and neuropathological changes associated with combined exposure to PB and PER. Method: Wild-type CD1 mice were exposed to 2mg/kg PB and 200 mg/kg of PER via i.p. in DMSO daily for 10 days and the control group received DMSO only. Following exposure, neurobehavioral profile were examined using the Rotarod test to assess motor deficits, the Open Field test for anxiety-related changes and the Morris Water Maze test to assess spatial memory. Mice were subsequently euthanized for proteomic and histopathological studies. Results: Mice exposed to PB and PER over 10 days showed an increase in anxiety-like behavior and delayed cognitive impairment compared to control mice that received vehicle only. Hence, GW agent exposed mice recapitulate the chronic and delayed emergence of the cognitive impairment associated with GWI. Comparative proteomic approaches showed changes in proteins associated with lipid metabolism and molecular transport in the brains of GW agent exposed mice compared to controls. Proteins associated with the endocrine and the immune systems were also altered, and dysfunction of these systems is a prominent feature of GWI. The presence of astrogliosis in the GW agent exposed mice compared to control mice further suggests an immune system imbalance, as is observed in GWI. Conclusion: These studies provide a broad perspective of the molecular disturbances driving the late pathology of this complex illness. Evaluation of the potential role of these biological functions in GWI will be useful in identifying molecular pathways to target for development of novel therapeutics for the treatment of GWI.
Funding:
This work is supported by a Congressionally Directed Medical Research Program award to Dr. Fiona Crawford (Grant#: GW080094).
Behavioral outcome in a mouse model of single and multiple concussions
Benoit Mouzon*†, Helena Chaytow*, Corbin Bachmeier*, Michael Mullan*†, and Fiona Crawford*†
*Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243
†James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL, 33612
Abstract:
Concussion or mild traumatic brain injury(mTBI), is the most common type of TBI. The World Health Organization (WHO) estimated that between 70 and 90% of head injuries that receive treatment are mild. Despite its prevalence, mTBI has only recently become accepted as a major health issue since the intense media attention brought to the public on the high incidence of TBI in military conflicts and on high-profile professional athletes. In the United States, every year, more than 2 million people sustain a TBI, principally as a result of falls (35.2%), motor vehicle accidents (17.3%), violence, sports-related injuries and nearby explosions on the battlefield. An understanding of the cellular mechanisms succeeding TBI is important as this is a major public health problem in industrialized countries.
The purpose of this study is to develop and characterize a novel mTBI model in rodents that replicates the pathological components or phases of human clinical mTBI. This model has several advantages over currently available rodent models of TBI like controlled cortical impact, weight drop, or the fluid percussion model. One advantage of this model is that the location of the hit on the midline allows the whole brain to be used for analyses. This new model is also of particular interest to investigate military or sports related concussions, where the soldier/athletes usually receive multiple hits over a relatively short period of their lifetime. Repetitive mTBI is believed to be associated with at least two devastating complications. An increase in brain vulnerability to a second concussive impact and/or 2) chronic cognitive impairments, such as chronic traumatic encephalopathy (CTE), which are often associated with accelerated neurodegeneration in specific brain regions. These data validate our model of mild head injury and demonstrate a temporal window of vulnerability to repetitive head trauma that results in behavioral dysfunction.
APP is Internalized After CD40 Ligation Which Increases Aβ Production
Ghania Ait-Ghezala1,2, Ekta Shah1, Jeremy Frieling1, Helena Chaytow1, Claude-Henry Volmar3,and Michael J. Mullan1,2
1Roskamp Institute, Sarasota, FL 34243. 2James A. Haley Veterans’ Hospital, Tampa, FL 33612. 3Scripps Research Institute, Jupiter, FL 33458.
ABSTRACT
CD40, a member of the tumor necrosis factor receptor superfamily, and its cognate ligand CD40L both have elevated levels in the brains of Alzheimer’s disease (AD) patients compared to controls. We have shown that pharmacological or genetic interruption of CD40/CD40L interaction results in mitigation of AD-like pathology in vivo in transgenic AD mouse models, and in vitro. Previously we showed that CD40L stimulation induces Ab production potentially through the g-secretase. Particularly we report an increase in levels of Ab (1-40) and Ab (1-42). We have also recently shown that CD40 ligation triggers internalization of APP, and that internalization by endocytosis is associated with increased Ab production. To further test whether lipid raft translocation of APP is indeed triggered by CD40 ligation, we have expressed a CD40/CD45 chimera in vitro. We will ultimately use this chimera to measure the impact of ligation on Ab production.
CD40 Ligand Deficiency Improves Rate of Functional Recovery Following Traumatic Brain Injury
Scott Ferguson1,2, Benoit Mouzon1,2, John Phillips1, Gogce Kayihan1,2, Helena Chaytow1, Alex Bishop1, Laila Abdullah1, Myles Mullan1, Venkatarajan Mathura1,2, Michael Mullan1,2, Fiona Crawford1,2
1Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243
2James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL, 33612
Abstract
Traumatic brain injury (TBI) has been diagnosed in 178,876 service members from 2000 to the first quarter of 2010. The neurobehavioral sequelae of TBI persist long after the injury, which consists of both a primary insult to the brain as well as secondary injury that occurs in the hours and days immediately thereafter. In order to find targets for therapeutic intervention we have analyzed the proteomic profile of the response to injury by Apolipoprotein E (APOE) transgenic mice. Polymorphisms in APOE are known to impact the outcome after TBI, with the APOE4 allele (and concomitant ApoE4 expressed protein) associated with worse outcome than ApoE3 following TBI.
Proteomic analysis of the response to injury by APOE transgenic mice revealed multiple pathways differentially regulated in APOE3 and APOE4 mice following injury, suggesting a potential role of those pathways in modulating the outcome from injury. One of these pathways involved CD40-related molecules. CD40 and its ligand, CD154, have been shown to be upregulated in patients following cerebral ischemia (Garlichs et al, 2003). A study by Ishikawa et al (2005) also showed CD40 and CD40 ligand deficient mice have reduced infarct volume in a mouse model of ischemia, and given that ischemic conditions are known to occur in the brain following TBI, we used CD40 ligand (CD40L) knockout mice (Jackson Laboratories) to study the effect of CD40 signaling in a CCI model of severe TBI.
Rotarod testing was used to evaluate neuromotor skills and the Barnes maze was employed to test spatial learning and memory. Our results showed that CD40L knockout mice showed an improved rate of functional recovery following TBI compared to wild type controls, as well as improved performance on both the Rotarod and Barnes maze tasks overall.
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