- Email: [email protected]
Modeling and elucidating the pathobiology of impact induced traumatic brain injury in the mouse
Tuesday, July 16, 2013: Poster Presentations: P3 P3-037
MODELING AND ELUCIDATING THE PATHOBIOLOGY OF BLAST-INDUCED TRAUMATIC BRAIN INJURY IN THE MOUSE
Andrew Fisher1, Chad Tagge1, Mark Wojnarowicz1, Xiao-Lei Zhang2, John Sullivan3, Chirag Upreti2, Cezar Goletiani2, Giorgi Maglakelidze2, Noel Casey4, Juliet Moncaster5, Olga Minaeva1, Kerry Cormier6, Caroline Kubilus6, David Chargin7, Andre Sharon8, Garth Hall9, Johnathan Kracht1, Jan Blusztajn5, Benjamin Wolozin1, Tsuneya Ikezu1, Christopher Nowinski1, Robert Stern1, Robert Cantu1, Rudolph Tanzi10, Neil Kowall1, Libor Velisek2, Robin Cleveland11, William Moss12, Patric Stanton2, Ann McKee1, Lee Goldstein5, 1Boston University, Boston, Massachusetts, United States; 2New York Medical College, Valhalla, New York, United States; 3NYMC, Valhalla, New York, United States; 4Boston University Center for Biometals & Metallomics, Boston, Massachusetts, United States; 5Boston University School of Medicine, Boston, Massachusetts, United States; 6Boston University, Bedford, Massachusetts, United States; 7Fraunhofer USA, Boston, Massachusetts, United States; 8 Boston University and Fraunhofer USA, Boston, Massachusetts, United States; 9University of Massachusetts Lowell, Lowell, Massachusetts, United States; 10Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts, United States; 11University of Oxford, Oxford, United Kingdom; 12Livermore National Laboratory, Livermore, California, United States. Contact e-mail: [email protected] Background: Traumatic brain injury (TBI) resulting from blast exposure (Wolf, 2009; Triton Report, 2011) affects an estimated 12-23% of the 2.4 million U.S. military servicemen and women deployed to Iraq and Afghanistan (Hoge, 2009; Terrio, 2009a). Blast-related TBI is a significant risk factor for persistent neuropsychiatric and cognitive impairment (Hoge, 2008a,b; Tanielian, 2008; Benzinger, 2009; Ling, 2009; Terrio, 2009a; Vasterling, 2009; Brenner, 2010; Hicks, 2010; MacDonald, 2011; Peskind, 2011). Our research team is uncovering evidence linking repetitive concussive TBI with later development of chronic traumatic encephalopathy (CTE), a devastating tau protein-linked chronic neurodegenerative disease (McKee, 2009; McKee, 2010; McKee, 2012). Methods: Blast mouse model, immunohistochemistry, Western blotting, electrophysiology, neurobehavior. Results: We report the first case series of postmortem brains from U.S. military veterans with histories of blast exposure and/or concussive injury. Examination of these military veteran brains revealed evidence of CTE neuropathology that was indistinguishable from the pathology in a comparison group of postmortem brains obtained from the youngest athletes with CTE studied to date. In the same study, we demonstrated that C57BL/6 mice exposed to a single blast also develop CTE-linked tau neuropathology, axonopathy, microvasculopathy, and neurodegeneration. Moreover, blastexposed mice also developed persistent learning and memory deficits that correlated with impaired axonal conduction and defective long-term synaptic plasticity. The neuropathology and neurobehavioral deficits we observed in blast-exposed mice closely recapitulate key clinical features observed in individuals affected by CTE (Baugh, 2012). Finally, we demonstrated that head immobilization during blast exposure blocked blast-induced neurobehavioral impairments, a finding that points to traumatic head acceleration as a major pathogenic contributor to blast-related CTE. Conclusions: Our data identify common determinants leading to CTE neuropathology in blast-exposed military veterans and head-injured athletes, and additionally, provide mechanistic evidence linking blast exposure to later development of CTElinked neuropathology and neurobehavioral deficits.
P3-038
A NOVEL PKC-DEPENDENT PHOSPHORYLATION OF DOUBLECORTIN: POTENTIAL IMPLICATIONS IN THE CONTEXT OF EXCITOTOXICITY
Julien Bruban1, Junichi Shioi2, Patty Lan3, Jindong Xu4, Nikolaos Robakis5, 1Mount Sinai School of Medicine, New York, New York, United States; 2Mount Sinai School of Medicine, New York, New York, United States; 3Mount Sinai School of Medicine, New York City, New York, United States; 4Mount Sinai School of Medicine, New York City, New York,
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United States; 5Mount Sinai Medical Center, New York City, New York, United States. Contact e-mail: [email protected] Background: Excitotoxicity is a neuronal condition marked by the overactivation of ionotropic glutamate receptors, leading to an excessive elevation of intracellular calcium levels and profound cytoskeletal reorganization. Such process has been implicated in several neurodegenerative disorders. Neurogenesis in the adult human brain has been shown and also implicated in neurodegenerative diseases. Doublecortin (Dcx) is a central molecule in neurogenesis, expressed by neuronal precursor cells and immature neurons in embryonic and adult brains. It functions as a classical microtubule -associated protein (MAP) whose phosphorylation regulates its affinity for microtubules, thus modulating microtubule dynamics involved in cytoskeletal architecture, mitotic spindle formation, microtubule-based transport or neuronal migration. Previous studies reported that Dcx can be phosphorylated by various kinases, such as Cdk5, JNK or MAPK. Methods: Western blot, Immunoprecipitation. Results: Here we describe a novel PKC-dependent phosphorylation of Dcx, which is transiently but rapidly induced by glutamate in primary cortical neurons. Interestingly, other agonists (NMDA, kainate, AMPA) of ionotropic glutamatereceptors or KCl-induced depolarization can also induce this phosphorylation in primary cultures. Besides, this phenomenon is dependent on the NR2B subunit of NMDA receptors since the Dcx phosphorylation was abolished by NMDA receptor inhibitors (MK801, D-APV) or NR2B specific inhibitor (Ifenprodil). Moreover, EGTA or the VGCC inhibitor Nifedipine completely blocked the phosphorylation, which was also induced by calcium ionophores, indicative of a calcium-dependent phenomenon. Finally, the Dcx phosphorylation was abolished by the PKC inhibitor chelerythrine, which confirms for the first time the predicted Dcx phosphorylation by PKC. Conclusions: These data provide new insight into the mechanisms regulating DCX phosphorylation. Also, it demonstrates a potential role for Dcx in immature neuron during excitotoxic process and raises the possibility that Dcx-positive cells may have functional significance in the pathophysiology of various neurodegenerative diseases. P3-039
MODELING AND ELUCIDATING THE PATHOBIOLOGY OF IMPACT INDUCED TRAUMATIC BRAIN INJURY IN THE MOUSE
Chad Tagge1, Andrew Fisher1, Noel Casey2, Mark Wojnarowicz1, Juliet Moncaster3, Olga Minaeva1, Amanda Gaudreau1, Garth Hall4, William Moss5, Thor Stein6, Ann McKee1, Neil Kowall1, Lee Goldstein3, 1 Boston University, Boston, Massachusetts, United States; 2Boston University Center for Biometals & Metallomics, Boston, Massachusetts, United States; 3Boston University School of Medicine, Boston, Massachusetts, United States; 4University of Massachusetts Lowell, Lowell, Massachusetts, United States; 5Livermore National Laboratory, Livermore, California, United States; 6Boston VA Medical Center, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Traumatic brain injury (TBI) ranks among the leading causes of traumatic death and is a leading cause of serious long-term disability. Each year over 1.5 million Americans sustain traumatic brain injuries. Recent case series point to impact-induced TBI and repetitive concussion as predisposing factors that increase the risk of developing the newly-recognized neurodegenerative disorder chronic traumatic encephalopathy (CTE). The neuropathology of this disorder includes tau-associated neurofibrillary tangles in a striking perivascular and deep sulcal distribution, widespread myelinated fiber loss, and neuroinflammation. We hypothesize that the biomechanical forces transmitted to structures in the brain during closed-head impact-induced TBI generates shearing forces that disrupt microvascular integrity, activate neuroinflammatory responses, and initiating pathogenic cascades that lead to persistent TBI and late-emerging CTE. Methods: To investigate the connection between TBI and CTE, we have developed a mouse model to mimic impact-induced TBI. The model allows for versatility by being able to vary the intensity and recurrence of the impact. The post-mortem techniques used to characterize focal tauopathy and neuroinflammation consist of comprehensive neuropathological analysis and immunophenotyping along with metallomic imaging to assess alternation
P566
Tuesday, July 16, 2013: Poster Presentations: P3
in microvascular integrity. Results: Results from the studies will advance understanding of impact-induced TBI and later development of CTE. Insights gained through this investigation will facilitate development of needed diagnostics and therapeutics for these devastating disorders. Conclusions: Our data identify common determinants leading to CTE neuropathology in impact head-injured athletes, and additionally, provide mechanistic evidence linking impact TBI to later development of CTElinked neuropathology and neurobehavioral deficits. P3-040
INTRACEREBROVENTRICULAR ADMINISTRATION OF STREPTOZOTOCIN EXACERBATES COGNITIVE DEFICITS AND BRAIN ABNORMALITIES OF 3XTG-AD MICE
Yanxing Chen1, 1Huazhong University of Science & Technology, Wuhan, China. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is multifactorial and involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose/energy metabolism. Methods: we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month old 3xTg-AD mice, a widely used transgenic (Tg) mouse model of AD, and studied the effect of STZ on cognitive function, as well as tau phosphorylation, Ab accumulation, and other related abnormalities in the mouse brains 3-6 weeks later. Results: We found that the intracerebroventricular (icv) administration of STZ exacerbated impairment of short-term memory and spatial reference memory in 3xTg-AD mice. Furthermore, an increase of tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease of synaptic plasticity and amyloid b peptides in the brain were observed after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases and apoptosis, was altered, suggesting that brain STZ administration disturbs multiple metabolic and cell signaling pathways in the 3xTg-AD brain. Conclusions: These findings demonstrate the role of metabolic insult in AD pathology. P3-041
CONTRIBUTION OF ALZHEIMER’S DISEASE AND LEWY BODY PATHOLOGY TO BEHAVIOR AND COGNITION IN LEWY BODY DEMENTIAS
Paul Francis1, Tibor Hortobagyi1, Johannes Attems2, Dag Aarsland1, Clive Ballard3, John O’Brein4, David Whitfield1, Amani Alghamdi1, Julie Vallortigara5, 1King’s College London, London, United Kingdom; 2 Newcastle University, Newcastle upon Tyne, United Kingdom; 3Kings College London, London, United Kingdom; 4Newcastle University, Newcastle, United Kingdom; 5King’s College London, London, United Kingdom. Contact e-mail: [email protected] Background: Lewy body dementias, including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are common disorders with both cognitive dysfunction behavioural and mood disturbances. In addition to cortical pathology featuring alpha synuclein there is also a considerable but variable Alzheimer pathology. The relative contributions of these different pathologies to particularly disturbances of mood and behaviour are not well understood. Methods: The demographic details of the cases examined are shown in Table 1. Using standard diagnostic protocols for Alzheimer’s disease and alpha synuclein pathology semi-quantitative scores for plaques, tangles and alpha synuclein pathology were obtained for frontal (BA9), parietal (BA40), temporal (BA21) and anterior cingulate (BA24) cortices (each scored as 0-3). These scores were summed to give an overall pathology score (0-9) and correlated with scores for cognition (MMSE) and behaviour/mood scores for depression, agitation/aggression, hallucinations and delusions. Results: Results for the summated pathology are shown in Table divided according to the clinical diagnosis. In all regions there was a significant difference across the diagnostic groups (ANOVA, p<0.05). All summary pathology scores correlated across the four regions (r>0.72, P<0.05 in each case). Classification of MMSE scores into mild, moderate and severe identified significant differences in mean summary pathology scores for each region (ANOVA, p<0.05). MMSE score at the last interview
before death correlated with summary pathology score in only BA40 (r¼ -0.34, p¼ 0.011). Of behaviour/mood scores only depression was related to summary pathology score in BA21 (P<0.05). Conclusions: Taken together these results indicate that the burden of pathology of all types in a region contributes to cognitive impairment in Lewy body dementias but pathology in parietal cortex seems particularly important. Summary pathology contributes less to disturbances of behaviour and mood.
Age (y)
Gender M/F PMD (h)
Control (25) 79.7 6 7.6 14/11 PDD (34) 79.9 6 6.0 12/22 DLB (55) 81.7 6 6.5 39/16 AD (16) 88.1 6 7.8 5/11
Control (25) PDD (34) DLB (55) AD (16)
P3-042
Braak CERAD
35.4 6 22.3 0-4 33.5 6 15.6 0-5 39.8 6 27.8 1-6 25.2 6 21.6 4-6
Cort LB
0.17 6 0.38 060 1.03 6 1.06 10.6 6 5.7 1.73 6 1.10 13.5 6 4.6 1.78 6 1.13
Summary pathology BA9
Summary pathology BA24
Summary pathology BA40
Summary pathology BA21
0.52 6 0.85 2.78 6 1.85 4.18 6 2.00 5.50 6 0.97
0.38 6 1.07 3.35 6 1.92 4.69 6 2.23 3.27 6 2.60
0.35 6 0.67 2.33 6 1.75 3.85 6 2.14 5.56 6 1.09
0.44 6 0.73 2.10 6 1.54 4.81 6 2.29 5.80 6 1.01
b-N-METHYLAMINO-L-ALANINE COULD BE INVOLVED IN ALZHEIMER’S NEUROFIBRILLARY PATHOLOGY IN AMYOTROPHIC LATERAL SCLEROSIS– PARKINSONISM DEMENTIA COMPLEX
Mohammad Arif1, Inge Grundke-Iqbal2, Khalid Iqbal2, 1NYS Institute for Basic Research, Staten Island, New York, United States; 2New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States. Contact e-mail: [email protected] Background: Amyotrophic lateral sclerosis-Parkinsonism dementia complex (ALS/PDC) is a neurodegenerative disease with features of ALS, Parkinsonism, and Alzheimer disease characterized by neurofibrillary tangles composed of abnormally hyperphosphorylated tau. b- N -methylamino- L -alanine (BMAA) has long been suspected to be involved in the etiology of ALS/PDC, but the mechanism underlying BMAA leading to tau hyperphosphorylation was not clearly understood. Methods: In the present study, we used the mouse E18 hippocampal primary neuronal cultures and metabolically active rat hippocampal slices in artificial CSF to examine the effects of BMAA on protein phosphatase 2A (PP2A) signaling and tau phosphorylation. Furthermore, we examined the PP2A activity and tau hyperphosphorylation in BMAA-infused rat brain and in the postmortem brain tissue from ALS/PDC cases. Results: BMAA treatment significantly decreased PP2A activity with concomitant increase of several tau kinase activities and tau hyperphosphorylation in primary neuronal cultures, metabolically active brain slices and in vivo in rat brain. The level of tau hyperphosphorylation was increased in ALS/PDC brain as compared to controls. In addition, the level of phospho-tyrosine (Tyr 307) PP2A was elevated in BMAA-treated rat brain and in ALS/PDC brain. Conclusions: These findings suggest that BMAA could be involved in the etiopathogenesis of ALS/PDC through inhibition of PP2A activity. P3-043
THE INCREASED SUSCEPTIBILITY TO OXIDATIVE DEATH OF LYMPHOCYTES FROM PEOPLE WITH ALZHEIMER’S DISEASE CORRELATES WITH THE SEVERITY OF DEMENTIA AND IS SPECIFIC FOR OXIDATIVE DAMAGE
Daniela P Ponce1, Felipe Salech1, Monica Silva1, Chengjie Xiong2, Catherine Roe3, Mauricio Henriquez1, Nicole Rogers1, Andrew Quest1, Maria Behrens4, 1Universidad de Chile, Santiago, Chile; 2Washington University School of Medicine, St. Louis, Missouri, United States;
MODELING AND ELUCIDATING THE PATHOBIOLOGY OF BLAST-INDUCED TRAUMATIC BRAIN INJURY IN THE MOUSE
Andrew Fisher1, Chad Tagge1, Mark Wojnarowicz1, Xiao-Lei Zhang2, John Sullivan3, Chirag Upreti2, Cezar Goletiani2, Giorgi Maglakelidze2, Noel Casey4, Juliet Moncaster5, Olga Minaeva1, Kerry Cormier6, Caroline Kubilus6, David Chargin7, Andre Sharon8, Garth Hall9, Johnathan Kracht1, Jan Blusztajn5, Benjamin Wolozin1, Tsuneya Ikezu1, Christopher Nowinski1, Robert Stern1, Robert Cantu1, Rudolph Tanzi10, Neil Kowall1, Libor Velisek2, Robin Cleveland11, William Moss12, Patric Stanton2, Ann McKee1, Lee Goldstein5, 1Boston University, Boston, Massachusetts, United States; 2New York Medical College, Valhalla, New York, United States; 3NYMC, Valhalla, New York, United States; 4Boston University Center for Biometals & Metallomics, Boston, Massachusetts, United States; 5Boston University School of Medicine, Boston, Massachusetts, United States; 6Boston University, Bedford, Massachusetts, United States; 7Fraunhofer USA, Boston, Massachusetts, United States; 8 Boston University and Fraunhofer USA, Boston, Massachusetts, United States; 9University of Massachusetts Lowell, Lowell, Massachusetts, United States; 10Massachusetts General Hospital/Harvard Medical School, Charlestown, Massachusetts, United States; 11University of Oxford, Oxford, United Kingdom; 12Livermore National Laboratory, Livermore, California, United States. Contact e-mail: [email protected] Background: Traumatic brain injury (TBI) resulting from blast exposure (Wolf, 2009; Triton Report, 2011) affects an estimated 12-23% of the 2.4 million U.S. military servicemen and women deployed to Iraq and Afghanistan (Hoge, 2009; Terrio, 2009a). Blast-related TBI is a significant risk factor for persistent neuropsychiatric and cognitive impairment (Hoge, 2008a,b; Tanielian, 2008; Benzinger, 2009; Ling, 2009; Terrio, 2009a; Vasterling, 2009; Brenner, 2010; Hicks, 2010; MacDonald, 2011; Peskind, 2011). Our research team is uncovering evidence linking repetitive concussive TBI with later development of chronic traumatic encephalopathy (CTE), a devastating tau protein-linked chronic neurodegenerative disease (McKee, 2009; McKee, 2010; McKee, 2012). Methods: Blast mouse model, immunohistochemistry, Western blotting, electrophysiology, neurobehavior. Results: We report the first case series of postmortem brains from U.S. military veterans with histories of blast exposure and/or concussive injury. Examination of these military veteran brains revealed evidence of CTE neuropathology that was indistinguishable from the pathology in a comparison group of postmortem brains obtained from the youngest athletes with CTE studied to date. In the same study, we demonstrated that C57BL/6 mice exposed to a single blast also develop CTE-linked tau neuropathology, axonopathy, microvasculopathy, and neurodegeneration. Moreover, blastexposed mice also developed persistent learning and memory deficits that correlated with impaired axonal conduction and defective long-term synaptic plasticity. The neuropathology and neurobehavioral deficits we observed in blast-exposed mice closely recapitulate key clinical features observed in individuals affected by CTE (Baugh, 2012). Finally, we demonstrated that head immobilization during blast exposure blocked blast-induced neurobehavioral impairments, a finding that points to traumatic head acceleration as a major pathogenic contributor to blast-related CTE. Conclusions: Our data identify common determinants leading to CTE neuropathology in blast-exposed military veterans and head-injured athletes, and additionally, provide mechanistic evidence linking blast exposure to later development of CTElinked neuropathology and neurobehavioral deficits.
P3-038
A NOVEL PKC-DEPENDENT PHOSPHORYLATION OF DOUBLECORTIN: POTENTIAL IMPLICATIONS IN THE CONTEXT OF EXCITOTOXICITY
Julien Bruban1, Junichi Shioi2, Patty Lan3, Jindong Xu4, Nikolaos Robakis5, 1Mount Sinai School of Medicine, New York, New York, United States; 2Mount Sinai School of Medicine, New York, New York, United States; 3Mount Sinai School of Medicine, New York City, New York, United States; 4Mount Sinai School of Medicine, New York City, New York,
P565
United States; 5Mount Sinai Medical Center, New York City, New York, United States. Contact e-mail: [email protected] Background: Excitotoxicity is a neuronal condition marked by the overactivation of ionotropic glutamate receptors, leading to an excessive elevation of intracellular calcium levels and profound cytoskeletal reorganization. Such process has been implicated in several neurodegenerative disorders. Neurogenesis in the adult human brain has been shown and also implicated in neurodegenerative diseases. Doublecortin (Dcx) is a central molecule in neurogenesis, expressed by neuronal precursor cells and immature neurons in embryonic and adult brains. It functions as a classical microtubule -associated protein (MAP) whose phosphorylation regulates its affinity for microtubules, thus modulating microtubule dynamics involved in cytoskeletal architecture, mitotic spindle formation, microtubule-based transport or neuronal migration. Previous studies reported that Dcx can be phosphorylated by various kinases, such as Cdk5, JNK or MAPK. Methods: Western blot, Immunoprecipitation. Results: Here we describe a novel PKC-dependent phosphorylation of Dcx, which is transiently but rapidly induced by glutamate in primary cortical neurons. Interestingly, other agonists (NMDA, kainate, AMPA) of ionotropic glutamatereceptors or KCl-induced depolarization can also induce this phosphorylation in primary cultures. Besides, this phenomenon is dependent on the NR2B subunit of NMDA receptors since the Dcx phosphorylation was abolished by NMDA receptor inhibitors (MK801, D-APV) or NR2B specific inhibitor (Ifenprodil). Moreover, EGTA or the VGCC inhibitor Nifedipine completely blocked the phosphorylation, which was also induced by calcium ionophores, indicative of a calcium-dependent phenomenon. Finally, the Dcx phosphorylation was abolished by the PKC inhibitor chelerythrine, which confirms for the first time the predicted Dcx phosphorylation by PKC. Conclusions: These data provide new insight into the mechanisms regulating DCX phosphorylation. Also, it demonstrates a potential role for Dcx in immature neuron during excitotoxic process and raises the possibility that Dcx-positive cells may have functional significance in the pathophysiology of various neurodegenerative diseases. P3-039
MODELING AND ELUCIDATING THE PATHOBIOLOGY OF IMPACT INDUCED TRAUMATIC BRAIN INJURY IN THE MOUSE
Chad Tagge1, Andrew Fisher1, Noel Casey2, Mark Wojnarowicz1, Juliet Moncaster3, Olga Minaeva1, Amanda Gaudreau1, Garth Hall4, William Moss5, Thor Stein6, Ann McKee1, Neil Kowall1, Lee Goldstein3, 1 Boston University, Boston, Massachusetts, United States; 2Boston University Center for Biometals & Metallomics, Boston, Massachusetts, United States; 3Boston University School of Medicine, Boston, Massachusetts, United States; 4University of Massachusetts Lowell, Lowell, Massachusetts, United States; 5Livermore National Laboratory, Livermore, California, United States; 6Boston VA Medical Center, Boston, Massachusetts, United States. Contact e-mail: [email protected] Background: Traumatic brain injury (TBI) ranks among the leading causes of traumatic death and is a leading cause of serious long-term disability. Each year over 1.5 million Americans sustain traumatic brain injuries. Recent case series point to impact-induced TBI and repetitive concussion as predisposing factors that increase the risk of developing the newly-recognized neurodegenerative disorder chronic traumatic encephalopathy (CTE). The neuropathology of this disorder includes tau-associated neurofibrillary tangles in a striking perivascular and deep sulcal distribution, widespread myelinated fiber loss, and neuroinflammation. We hypothesize that the biomechanical forces transmitted to structures in the brain during closed-head impact-induced TBI generates shearing forces that disrupt microvascular integrity, activate neuroinflammatory responses, and initiating pathogenic cascades that lead to persistent TBI and late-emerging CTE. Methods: To investigate the connection between TBI and CTE, we have developed a mouse model to mimic impact-induced TBI. The model allows for versatility by being able to vary the intensity and recurrence of the impact. The post-mortem techniques used to characterize focal tauopathy and neuroinflammation consist of comprehensive neuropathological analysis and immunophenotyping along with metallomic imaging to assess alternation
P566
Tuesday, July 16, 2013: Poster Presentations: P3
in microvascular integrity. Results: Results from the studies will advance understanding of impact-induced TBI and later development of CTE. Insights gained through this investigation will facilitate development of needed diagnostics and therapeutics for these devastating disorders. Conclusions: Our data identify common determinants leading to CTE neuropathology in impact head-injured athletes, and additionally, provide mechanistic evidence linking impact TBI to later development of CTElinked neuropathology and neurobehavioral deficits. P3-040
INTRACEREBROVENTRICULAR ADMINISTRATION OF STREPTOZOTOCIN EXACERBATES COGNITIVE DEFICITS AND BRAIN ABNORMALITIES OF 3XTG-AD MICE
Yanxing Chen1, 1Huazhong University of Science & Technology, Wuhan, China. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is multifactorial and involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose/energy metabolism. Methods: we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month old 3xTg-AD mice, a widely used transgenic (Tg) mouse model of AD, and studied the effect of STZ on cognitive function, as well as tau phosphorylation, Ab accumulation, and other related abnormalities in the mouse brains 3-6 weeks later. Results: We found that the intracerebroventricular (icv) administration of STZ exacerbated impairment of short-term memory and spatial reference memory in 3xTg-AD mice. Furthermore, an increase of tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease of synaptic plasticity and amyloid b peptides in the brain were observed after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases and apoptosis, was altered, suggesting that brain STZ administration disturbs multiple metabolic and cell signaling pathways in the 3xTg-AD brain. Conclusions: These findings demonstrate the role of metabolic insult in AD pathology. P3-041
CONTRIBUTION OF ALZHEIMER’S DISEASE AND LEWY BODY PATHOLOGY TO BEHAVIOR AND COGNITION IN LEWY BODY DEMENTIAS
Paul Francis1, Tibor Hortobagyi1, Johannes Attems2, Dag Aarsland1, Clive Ballard3, John O’Brein4, David Whitfield1, Amani Alghamdi1, Julie Vallortigara5, 1King’s College London, London, United Kingdom; 2 Newcastle University, Newcastle upon Tyne, United Kingdom; 3Kings College London, London, United Kingdom; 4Newcastle University, Newcastle, United Kingdom; 5King’s College London, London, United Kingdom. Contact e-mail: [email protected] Background: Lewy body dementias, including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), are common disorders with both cognitive dysfunction behavioural and mood disturbances. In addition to cortical pathology featuring alpha synuclein there is also a considerable but variable Alzheimer pathology. The relative contributions of these different pathologies to particularly disturbances of mood and behaviour are not well understood. Methods: The demographic details of the cases examined are shown in Table 1. Using standard diagnostic protocols for Alzheimer’s disease and alpha synuclein pathology semi-quantitative scores for plaques, tangles and alpha synuclein pathology were obtained for frontal (BA9), parietal (BA40), temporal (BA21) and anterior cingulate (BA24) cortices (each scored as 0-3). These scores were summed to give an overall pathology score (0-9) and correlated with scores for cognition (MMSE) and behaviour/mood scores for depression, agitation/aggression, hallucinations and delusions. Results: Results for the summated pathology are shown in Table divided according to the clinical diagnosis. In all regions there was a significant difference across the diagnostic groups (ANOVA, p<0.05). All summary pathology scores correlated across the four regions (r>0.72, P<0.05 in each case). Classification of MMSE scores into mild, moderate and severe identified significant differences in mean summary pathology scores for each region (ANOVA, p<0.05). MMSE score at the last interview
before death correlated with summary pathology score in only BA40 (r¼ -0.34, p¼ 0.011). Of behaviour/mood scores only depression was related to summary pathology score in BA21 (P<0.05). Conclusions: Taken together these results indicate that the burden of pathology of all types in a region contributes to cognitive impairment in Lewy body dementias but pathology in parietal cortex seems particularly important. Summary pathology contributes less to disturbances of behaviour and mood.
Age (y)
Gender M/F PMD (h)
Control (25) 79.7 6 7.6 14/11 PDD (34) 79.9 6 6.0 12/22 DLB (55) 81.7 6 6.5 39/16 AD (16) 88.1 6 7.8 5/11
Control (25) PDD (34) DLB (55) AD (16)
P3-042
Braak CERAD
35.4 6 22.3 0-4 33.5 6 15.6 0-5 39.8 6 27.8 1-6 25.2 6 21.6 4-6
Cort LB
0.17 6 0.38 060 1.03 6 1.06 10.6 6 5.7 1.73 6 1.10 13.5 6 4.6 1.78 6 1.13
Summary pathology BA9
Summary pathology BA24
Summary pathology BA40
Summary pathology BA21
0.52 6 0.85 2.78 6 1.85 4.18 6 2.00 5.50 6 0.97
0.38 6 1.07 3.35 6 1.92 4.69 6 2.23 3.27 6 2.60
0.35 6 0.67 2.33 6 1.75 3.85 6 2.14 5.56 6 1.09
0.44 6 0.73 2.10 6 1.54 4.81 6 2.29 5.80 6 1.01
b-N-METHYLAMINO-L-ALANINE COULD BE INVOLVED IN ALZHEIMER’S NEUROFIBRILLARY PATHOLOGY IN AMYOTROPHIC LATERAL SCLEROSIS– PARKINSONISM DEMENTIA COMPLEX
Mohammad Arif1, Inge Grundke-Iqbal2, Khalid Iqbal2, 1NYS Institute for Basic Research, Staten Island, New York, United States; 2New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, United States. Contact e-mail: [email protected] Background: Amyotrophic lateral sclerosis-Parkinsonism dementia complex (ALS/PDC) is a neurodegenerative disease with features of ALS, Parkinsonism, and Alzheimer disease characterized by neurofibrillary tangles composed of abnormally hyperphosphorylated tau. b- N -methylamino- L -alanine (BMAA) has long been suspected to be involved in the etiology of ALS/PDC, but the mechanism underlying BMAA leading to tau hyperphosphorylation was not clearly understood. Methods: In the present study, we used the mouse E18 hippocampal primary neuronal cultures and metabolically active rat hippocampal slices in artificial CSF to examine the effects of BMAA on protein phosphatase 2A (PP2A) signaling and tau phosphorylation. Furthermore, we examined the PP2A activity and tau hyperphosphorylation in BMAA-infused rat brain and in the postmortem brain tissue from ALS/PDC cases. Results: BMAA treatment significantly decreased PP2A activity with concomitant increase of several tau kinase activities and tau hyperphosphorylation in primary neuronal cultures, metabolically active brain slices and in vivo in rat brain. The level of tau hyperphosphorylation was increased in ALS/PDC brain as compared to controls. In addition, the level of phospho-tyrosine (Tyr 307) PP2A was elevated in BMAA-treated rat brain and in ALS/PDC brain. Conclusions: These findings suggest that BMAA could be involved in the etiopathogenesis of ALS/PDC through inhibition of PP2A activity. P3-043
THE INCREASED SUSCEPTIBILITY TO OXIDATIVE DEATH OF LYMPHOCYTES FROM PEOPLE WITH ALZHEIMER’S DISEASE CORRELATES WITH THE SEVERITY OF DEMENTIA AND IS SPECIFIC FOR OXIDATIVE DAMAGE
Daniela P Ponce1, Felipe Salech1, Monica Silva1, Chengjie Xiong2, Catherine Roe3, Mauricio Henriquez1, Nicole Rogers1, Andrew Quest1, Maria Behrens4, 1Universidad de Chile, Santiago, Chile; 2Washington University School of Medicine, St. Louis, Missouri, United States;