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Roskamp Institute Articles Better Science. Real Discovery.

July 9, 2012

Journal club

Filed under: Uncategorized — Tags: , — Gogce Crynen @ 12:48 pm

Event: Journal Club ” Identification and Validation of Target Pathways Influencing Outcome After Traumatic Brain Injury.”

One of our PhD students has submitted his final thesis which he will be presenting at this week’s Journal Club. The title is “Identification and Validation of Target Pathways Influencing Outcome After Traumatic Brain Injury.”

We hope you can join us at the Roskamp Institute at 4pm this Friday.

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.
The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949.

February 14, 2012

Event: Journal Club ” Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats. “

Filed under: Uncategorized — Tags: , , — Gogce Crynen @ 12:43 pm

Zuchra Zakirova will be presenting the paper on Friday (2/17/2012) at 4:00 PM in Roskamp Institute.
Title:  “Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats ”

Truettner J.S., Alonso O.F., Bramlett H.M., Dietrich W.D. “Therapeutic hypothermia alters microRNA responses to traumatic brain injury in rats”. J Cereb Blood Flow Metab. 2011 Sep;31(9):1897-907

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.
The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

October 10, 2011

Event: Journal Club Early TBI-Induced Cytokine Alterations are Similarly Detected by Two Distinct Methods of Multiplex Assay “

Filed under: Uncategorized — Tags: , — Gogce Crynen @ 5:20 pm


Scott Ferguson will be presenting the paper on Friday (10/14/2011) at 4:00 PM in Roskamp Institute.

Title: “Early TBI-Induced Cytokine Alterations are Similarly Detected by Two Distinct Methods of Multiplex Assay ”

Mukherjee, S., Katki, K., Arisi, G. M., Foresti, M. L. and Shapiro, L. A., Early TBI-Induced Cytokine Alterations are Similarly Detected by Two Distinct Methods of Multiplex Assay. Front Mol Neurosci. 4, 21.Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

September 28, 2011

Event: Journal Club ” The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats ” and ” Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor”

Filed under: Uncategorized — Tags: , , — Gogce Crynen @ 10:10 pm

Benoit Mouzon will be presenting the paper on Friday (9/30/2011) at 4:00 PM in Roskamp Institute.

Title: ” The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats ” and ” Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor”

The potential role of JAK2/STAT3 pathway on the anti-apoptotic effect of recombinant human erythropoietin (rhEPO) after experimental traumatic brain injury of rats. Zhao J, Li G, Zhang Y, Su X, Hang C. Cytokine. 2011 Aug 13.

Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. Xiong Y, Mahmood A, Qu C, Kazmi H, Zhang ZG, Noguchi CT, Schallert T, Chopp M. J Neurotrauma. 2010 Jan;27(1):205-15.

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

August 30, 2011

Event: Journal Club “Stress and traumatic brain injury: a behavioral, proteomics, and histological study “

Filed under: Uncategorized — Tags: , , , , — Gogce Crynen @ 9:51 am

Scott Ferguson will be presenting the paper on Friday (9/2/2011) at 4:00 PM in Roskamp Institute.

Title: ” Stress and traumatic brain injury: a behavioral, proteomics, and histological study.”

Kwon, S. K., Kovesdi, E., Gyorgy, A. B., Wingo, D., Kamnaksh, A., Walker, J., Long, J. B. and Agoston, D. V.,2011. Stress and traumatic brain injury: a behavioral, proteomics, and histological study. Front Neurol. 2, 12.

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

April 15, 2011

VA Research Day, at James A. Haley Veterans’ Hospital, on April 14th 2011

Filed under: Uncategorized — Tags: , , , — Gogce Crynen @ 9:55 am

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.

April 4, 2011

Event: Journal Club ” Mechanical Tissue Resuscitation Treatment Reduces Brain Tissue Volume and Intracerebral Hemorrhage and Increases Blood Perfusion in a Traumatic Brain Injury Model in Swine” and “Efficacy and mechanisms of vacuum-assisted closure (VAC) therapy in promoting wound healing: a rodent model”

Filed under: Uncategorized — Tags: , — Gogce Crynen @ 5:27 pm

Benoit Mouzon will be presenting the paper on Friday (4/08/2011) at 4:00 PM in Roskamp Institute.

Title: ” Mechanical Tissue Resuscitation Treatment Reduces Brain Tissue Volume and Intracerebral Hemorrhage and Increases Blood Perfusion in a Traumatic Brain Injury Model in Swine” and “Efficacy and mechanisms of vacuum-assisted closure (VAC) therapy in promoting wound healing: a rodent model”

2010, Conference paper, http://handle.dtic.mil/100.2/ADA532538 and J Plast Reconstr Aesthet Surg. 2009 Oct;62(10):1331-8. Epub 2008 Jul 9, respectively.

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

February 7, 2011

Event: Journal Club “Neurogenesis in Adult Human Brain after Traumatic Brain Injury. ”

Filed under: Uncategorized — Tags: , — Gogce Crynen @ 3:39 pm

Scott Ferguson will be presenting the paper on Friday (2/11/2011) at 4:00 PM in Roskamp Institute.

Title: Neurogenesis in Adult Human Brain after Traumatic Brain Injury.

J Neurotrauma. 2011 Jan 30. [Epub ahead of print]

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

January 4, 2011

Event: Journal Club “Synergistic benefits of erythropoietin and simvastatin after traumatic brain injury”

Filed under: Uncategorized — Tags: , , — Gogce Crynen @ 1:56 pm


Helena Chaytow will be presenting the paper on Friday (1/7/2011) at 4:00 PM in Roskamp Institute.

Title: Synergistic benefits of erythropoietin and simvastatin after traumatic brain injury

Brain Res. 2010 Nov 11;1360:177-92. Epub 2010 Sep 15.

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

November 16, 2010

Event: Journal Club, Neuroscience San Diego 2010 meeting highlights

Filed under: Uncategorized — Tags: , , , , — Gogce Crynen @ 10:51 am
Please join us at 4:00 pm this Friday at the Roskamp Institute for Journal Club. We will have a special presentation by Laila Abdullah, Scott Ferguson, and Benoit Mouzon of the highlights of the 2010 Society for Neuroscience conference.

Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

November 11, 2010

Event: Journal Club “Biochemical and neurochemical sequelae following mild traumatic brain injury: summary of experimental data and clinical implications”

Filed under: Uncategorized — Tags: — Gogce Crynen @ 11:32 am

Benoit Mouzon will be presenting the paper on Friday (11/12/2010) at 4:00 PM in Roskamp Institute.

Title: Biochemical and neurochemical sequelae following mild traumatic brain injury: summary of experimental data and clinical implications

Neurosurg Focus 29 (5):E1, 2010

Journal Club is held every Friday. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

September 8, 2010

Event: Journal Club “Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury”

Filed under: Uncategorized — Tags: , — Gogce Crynen @ 9:50 am

Scott Ferguson will be presenting the paper on Friday (9/10/2010) at Roskamp Institute.


Title:  Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury.

Journal of Neuroinflammation 2010, 7:41      doi:10.1186/1742-2094-7-41

Journal Club is held every Friday between 4 pm-5pm. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

August 23, 2010

Event: Journal Club “Is there a gender difference in mortality after TBI?”

Filed under: TBI — Tags: , — Gogce Crynen @ 1:16 pm

Benoit Mouzon will be presenting the following papers on Friday (8/27/2010) at Roskamp Institute.

Title:  Severe traumatic brain injury: is there a gender difference in mortality?

The American Journal of Surgery (2009) 197, 155–158.

And

Title: The Effect of Gender on Patients With Moderate to Severe Head Injuries

The Journal of Trauma 2009 Nov; 67 (5), 950-953.

Journal Club is held every Friday between 4 pm-5pm. For change in schedule please check our twitter account or facebook page.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

April 30, 2010

Roskamp Institute Poster Abstract from VA Reasearch Week

Filed under: Uncategorized — Tags: , , , , , , , , — Gogce Crynen @ 10:22 am

As I mentioned before, most of the PhD students and research assistants from our Institute participated in poster session  that was organized as a part of VA Research Week event series. Here you will find the abstract of our posters, enjoy :)

Development of the Barnes Maze as an Alternative to the Morris Water Maze Following TBI in Mice.

Scott Ferguson1,2, Benoit Mouzon1,2, John Phillips1, Vani Ganapapthi1, Alex Bishop1, Gogce Kayihan1,2, Venkatarajan Mathura1,2, Michael Mullan1,2 , Fiona Crawford1,2

1The Roskamp Institute, Sarasota, FL, USA; 2 James A Haley Veterans Administration, Tampa, FL, USA

Traumatic brain injury (TBI) is suffered by approximately 1.4 million people in the United States each year. TBI is the leading cause of death and disability in the most active population (under 45 years of age) in industrialized countries. Within the military, TBI is associated with 59% of blast-associated injuries seen at Walter Reed Army Medical Center, and between January 2003 and May 2005, 31% of all admissions to WRAMC had a brain injury. Apolipoprotein E (APOE) polymorphisms 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.   As part of our TBI research program we are exploring the molecular, neurobehavioral and neuropathological outcome after TBI in mouse models of injury, including APOE transgenic mice.

In order to evaluate differential outcomes of injury and its effects on motor skills and memory, we have optimized a series of neurobehavioral tests in mice.  The Rotarod test measures motor skill and learning via a programmable rotating bar.  Rotarod has shown the ability to distinguish between injured and uninjured mice, and has shown appropriate trends between differing levels of injury.  Morris water maze is a test of spatial memory and learning originally designed for rats but later adapted for mice.  APOE3 mice performed better than APOE4 mice in our Rotarod results, demonstrating an APOE genotype-dependent effect on motor function following TBI.  However, in the cognitive paradigm not only did we fail to detect any APOE genotype-dependent effects, we observed no significant differences in performance between injured and uninjured mice.  We therefore explored other cognitive paradigms for their ability to discriminate between injured and uninjured mice.

The Barnes maze is analogous to the Morris water maze in that it is also a test of spatial memory and learning, but because swimming is not involved it is associated with less stress than MWM typically induces in mice.  Others have shown that there is a strain-dependent effect on the ability of mice to learn the water maze task as well as the Barnes maze task.  Given that C57BL/6J mice are reported to perform better on the Barnes maze task, and this is the background strain utilized in our research, we optimized a paradigm of the Barnes maze for use in our TBI studies.  Our results show a statistically significant effect of injury on the spatial memory and learning of C57BL/6J wild type mice.  Future studies will re-examine the effect of APOE genotype on spatial memory following TBI using this test.

This research was funded by a Department of Defense award (W81XWH-07-1-0700) to Dr. Fiona Crawford and by the Roskamp Foundation

APP is Internalized After CD40 Ligation Which Increases Aβ Production

Ghania Ait-Ghezala, Jeremy Frieling, Myles Mullan, Claude-Henry Volmar, and Michael J. Mullan.

CD40, a member of the tumor necrosis factor receptor superfamily, and its cognate ligand CD40L are both elevated 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. Recently, we showed that CD40L stimulation could increase Aβ levels, but the mechanism causing this phenomenon is not known. Here we show that CD40 ligation triggers internalization of APP and that internalization by endocytosis is associated with increased Aβ production. Furthermore, anthocyanins, which are known to impact trafficking to and from lipid rafts, impair the production of Aβ by CD40L stimulated CD40. However, anthocyanins have no effect on CD40L treatment of a neuroblastoma cell line over-expressing the C-99 APP fragment suggesting that CD40L internalization has no effect on γ-secretase. This finding is consistent with previous data suggesting that endocytosis increases BACE activity. In summary, these data suggest that a general mechanism of increased Aβ generation may be lipid raft mediated internalization of APP allowing increased BACE activity on its substrate.

Neurobehavioral profiles of two mouse models of Gulf War Illness

Laila Abdullah1, Alex Bishop1, John Phillips1, Benoit Mouzon1,2, Scott Ferguson1,2, Vani Ganapathi1, Myles Mullan1,2, Ghania Ait-Ghezala PhD1,2, Michael Mullan MD, PhD1,2 and Fiona Crawford PhD1,2

Affiliations: 1Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, 2James A. Haley VA Hospital, 13000 Bruce B. Downs Blvd, Tampa, FL, 33612.

Background: Gulf War Illness (GWI) is a multisymptom condition associated with service in the 1990-1991 Persian Gulf War conflict and affects around 250,000 US veterans. It is largely attributed to combined exposure to pyridostigmine bromide (PB) and overuse of pesticides and insect repellants.  After nearly two decades, there is still no treatment for GWI and the underlying pathologic factors associated with the observed central nervous system (CNS)-based symptoms in veterans remain unclear.  Current GWI animal models do not demonstrate the full spectrum of neurobehavioral features reported to be associated with GWI, which makes it particularly difficult to explore the efficacy of possible therapeutic options.  Therefore, we tested two different treatment paradigms in order to establish a mouse model of GWI, which exhibits motor, cognitive and anxiety-related symptoms that are observed in veterans with this illness.  Methods: For model A, a previously established treatment paradigm was used which showed pathological changes suggestive of neurodegeneration, however extensive neurobehavioral profiling was not performed. Treated C57BL6 mice received oral administration of 1.3mg/kg of PB in water, dermal application of 0.13mg/kg of permethrin (PER) and 40 mg/kg of N-N-diethyl m-toluamide 2 (DEET) in 70% ethanol and 5 minutes of restrained stress daily for 28 days, whereas control mice received vehicle for the same duration.  For model B, a new treatment paradigm was developed where CD1 mice in the treatment group were administered 2mg/kg of PB and 200 mg/kg of PER via i.p. in DMSO daily for 10 days and the control group received DMSO only.  Following treatment, neurobehavioral profiles 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.  Results: In model A, treatment was associated with significant impairment in sensorimotor function and presence of anxiety-related behavior, but there was no deficit in spatial memory.  In model B, a delayed adverse effect of treatment was observed on the outcome measures of anxiety and spatial memory, but there was no evidence of sensorimotor impairment.  Conclusion: These findings suggest that combined exposure to PB and pesticides/insect repellents may lead to CNS-based effects in mice that mimic some of the clinical symptoms observed in veterans with GWI.  Additional studies are required to determine whether all three neurobehavioral features can be produced in one mouse model and whether these changes correlate with pathological features associated with neurodegeneration.

Acknowledgment: Funding for this research is provided by a Congressionally Directed Medical Research award (GW080094) to Dr. Fiona Crawford.

Proteomic identification of plasma TBI biomarkers

Benoit Mouzon1,2, Alex Bishop1, Gogce Kayihan1,2, Ben Katz1, Scott Ferguson1,2, Jon Reed1, Venkatarajan Mathura1, Michael Mullan1,2 and Fiona Crawford1,2

1Roskamp Institute, Sarasota, Florida

2James A. Haley Veterans’ Hospital, Tampa, Florida

Traumatic Brain Injury (TBI) is a major cause of mortality and morbidity in both military and civilian populations. The current lack of prognostic biomarkers for TBI confounds treatment and management of patients and is of increasing concern as the TBI population grows.  As part of our TBI research program we are generating brain and plasma proteomic profiles from APOE3 and APOE4 transgenic mice which demonstrate relatively favorable and unfavorable outcomes respectively, following TBI.  In this study we used proteomic approaches to identify the changes in plasma protein profiles in APOE3 and APOE4 mice following severe TBI, in order to determine peripheral biomarkers associated with a poor outcome after TBI.

Using a quantitative proteomics approach (isobaric tagging for relative and absolute quantitation – iTRAQ) we have identified proteins that are significantly modulated as a function of APOE genotype, injury and the interactive term of “genotype*injury”. Analysis of modulated plasma proteins revealed significant differences in proteomic response at 24 hours, 1 month and 3 months post injury across genotypes.  From these proteomic datasets we have identified 83 proteins at the 24 hour timepoint, 170 at 1 month and 129 at 3 months post TBI. For each timepoint, the identified proteins included those whose response was dependent on injury or the injury*genotype interaction, suggesting them as potential biomarkers of injury or outcome following injury.

In pilot validation studies, using antibody-based approaches in the original plasma from these mice, we have demonstrated the validity of our approach.  These preliminary data clearly demonstrate plasma protein changes that are not only injury-dependent but also interaction-dependent. The identified proteins include biomarkers that have been previously implicated in human TBI, and their time course and relationship to neurobehavior and pathology are now to be examined in these mouse models.  Importantly these results demonstrate the presence of TBI-dependent and interaction-dependent plasma proteins at a 3 months time point, which is a considerable time post-injury in the mouse model and will potentially be of significance for combat veterans receiving assessment at extended periods post-injury.  Furthermore, our identification of clusters of related proteins indicates disturbance of particular biological modules which increases their value beyond that of solitary biomarkers.  Clinical assays for many of these proteins are already established, which will facilitate translation of our findings from mouse to human.

The biomarker panels developed from this work will aid clinicians in the determination of diagnosis, prognosis, appropriate treatment and monitoring response to treatment, all of which are urgently needed in TBI management. The next step will be to investigate these potential biomarkers in human TBI patients and those studies will begin this year with the VA patient population and our clinical collaborators.

Acknowledgement:  This research was funded by a Department of Defense award (W81XWH-07-1-0700) to Dr. Fiona Crawford.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949


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