- Email: [email protected]
Graph Theory Metrics Of Resting State Networks In MCI And AD
Poster Presentations age was observed in normal, aMCI and eAD group, respectively, which Standardized Profile Score, Screening Score of RBMT, attension of MMSE, conceptualization, mental flexibility and total score of FAB in normal, Face recognition and Orientation of day of RBMT, Attention of MMSE and conceptualization of FAB in aMCI, and Delayed recall of a new route and Immediate recall of a message of RBMT, and conceptualization and programming of FAB in eAD.In the same stage of AD, cognitive dysfunction was difference from age.
P4-276
DIFFERENTIAL EXPRESSION OF CELL SURFACE PROTEINS IN HUMAN BONE MARROW MESENCHYMAL STEM CELLS CULTURED WITH OR WITHOUT BASIC FIBROBLAST GROWTH FACTOR CONTAINING MEDIUM
Sang Kwang Lee1, Youngtae Kim1, Sung-Soo Kim2, Jeong Hwa Lee1, Kun Cho1, Sang Sook Lee1, Zee-Won Lee1, Kyung-Hoon Kwon1, Young Hye Kim1, Haeyoung Suh-Kim3, Jong Shin Yoo1,4, Young Mok Park1,4, 1Korea Basic Science Istitute, Daejeon, Republic of Korea; 2Ajou University, Suwon, Republic of Korea; 3Ajou University, Suwon, Republic of Korea; 4Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea. Contact e-mail: [email protected] Background: Mesenchymal stem cells (MSCs) are multipotent cells, which have the capability to differentiate into various mesenchymal tissues such as bone, cartilage, fat, tendon, muscle, neurons and astrocytes. Mesenchymal stem cells (MSCs) transplanted at sites of nerve injury are thought to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. However, they tend to lose capability of multi-lineage differentiation after several passages. It is known that basic fibroblast growth factor (bFGF) increases growth rate, differentiation potential and morphological changes of MSCs in vitro. Objective: In this report, we have used two-dimensional electrophoresis (2-DE) coupled to mass spectrometry to identify differentially expressed proteins at the cell membrane level in MSCs growing in bFGF containing medium. Methods: The cell surface proteins isolated by the biotin-avidin affinity column were separated by 2-DE in triplicate experiments. A total of 15 differentially expressed proteins were identified by quadrupole-time of flight tandem mass spectrometry. Conclusion: Nine of the proteins were up-regulated and six proteins were down-regulated in the MSCs cultured with bFGF containing medium. The expression level of three actin-related proteins, F-actin-capping protein subunit alpha-1 (CAPZA1), actin-related protein 2/3 complex subunit 2 (ARPC2), and myosin regulatory light chain 2 (MRLC2), was confirmed by Western blot analysis. The results indicate that the expression levels of CAPZA1, ARPC2, and MRLC2 are important in bFGF-induced morphological change of MSCs. P4-277
GRAPH THEORY METRICS OF RESTING STATE NETWORKS IN MCI AND AD
Kelvin O. Lim1,2, Laura S. Hemmy1,2, Bryon A. Mueller1, Chris Bell1, Sue J. Rottunda2, Michael A. Kuskowski1,2, John R. McCarten1,2, 1University of Minnesota, Minneapolis, MN, USA; 2Veterans Affairs Medical Center, Minneapolis, MN, USA. Contact e-mail: [email protected] Background: Graph Theory provides a powerful tool for analyzing complex networks derived from resting fMRI. In recent work, graph theory has been successfully applied to differentiating networks of Alzheimer’s patients and healthy controls (Supekar et al., PLOS Computational Biology, 2008). Objective: In this preliminary study, we sought to determine if differences between AD subjects and MCI subjects could be detected using graph theory network analysis. Methods: Clinical data was obtained from the work-up of 41 subjects diagnosed with probable Alzheimer’s disease (AD; DSMIV/NINCDS-ADRDA criteria) and 16 subjects with Mild Cognitive Impairment (MCI; Peterson, 2006) presenting to a VA Medical Center Memory Loss Clinic. Diagnoses were determined through a systematic consensus diagnosis process based upon a standardized history, neurological exam, neuropsychological evaluation, occupational therapy evaluation, labs, and
e11
MRI protocol. Consensus was obtained from a neurologist, geropsychiatrist, internist, and neuropsychologist. Resting fMRI data was collected on a 1.5T system with TR¼2sec for 6minutes. Preprocessing was performed including registration and slice-time adjustment. Time courses were extracted from ninety regions sing an anatomical atlas and a wavelet analysis was applied to compute frequency dependent correlation matrices. The small-world metrics characteristic path length and clustering coefficient were computed for the frequency interval 0.12-0.06Hz averaged over a threshold range representing .1 to .3 of the maximum possible number of edges in the graph. Conclusion: Subjects were 93% male and aged an average of 77.83 (6.70 SD) years. Imaging was performed an average of 40.4 (MMSE; 29.2 SD) and 59.84 (neuropsychological tests; 58.1 SD) days difference from the clinical outcomes. No group differences were found for either graph metric. No associations were found between graph metrics and age or MMSE. It may be that these metrics have more potential as early indicators of pathology than in clinical staging and that our sample is too impaired. Future investigations should contrast MCI and normal samples. Limitations of this preliminary study include the small number of subjects and mostly male sample.
P4-278
THE ABETA OLIGOMER SELECTIVE ANTIBODY NAB61 RECOGNIZES ABETA OLIGOMERS IN THE AD AND APP TRANSGENIC MOUSE BRAINS AND NEUTRALIZES ABETA MEDIATED SYNAPTIC DYSFUNCTION
Johan Lundkvist1, Leo M. Kim2, Elin Gustafsson1, Elin Hagstro¨m1, Henrik Zetterberg3, Eric Hanse3, Gabriel Von Euler1, Sergey Leonov1, Jan Na¨slund1, Camilla Dahlqvist1, John Q. Trojanowski2, Virginia M.-Y. Lee2, 1 AstraZeneca, So¨derta¨lje, Sweden; 2University of Pennsylvania, Philadelphia, PA, USA; 3Go¨teborgs Universitet, Go¨teborg, Sweden. Contact e-mail: johan. [email protected] Background: Loss of synapses is a central neuroanatomical hallmark in Alzheimer’s disease (AD). A growing body of data suggests that soluble oligomeric forms rather than fibrillar deposits of Ab, comprise the primary synaptotoxic entity of Ab. Major support for this hypothesis comes from APP transgenic mice, which display behavioural deficits prior to plaque appearance. Administration of Nab61, a monoclonal antibody selective for oligomeric forms of Ab, attenuates behavioural deficits in TG2576 mice, suggesting that Ab oligomers indeed mediate synaptic dysfunction. Objective: To further explore the role of Ab oligomers in AD. Methods: In this study we have used Nab61 as a molecular tool to explore the presence of Ab oligomers in the AD brain, in TG2576 mice and as modulators of synaptic activity in cell culture models. Conclusion: We show that Ab oligomers, mainly composed of Ab42, are elevated both in the AD and TG2576 brains. Moreover, Nab61 prevents Ab -dendrite interactions and neutralizes Ab induced changes in spine morphology and synaptic plasticity. Combined these data provide support to the hypothesis that Ab oligomers contribute to the synaptic loss associated with AD. P4-279
COMPOUND SCREENING IN A DROSOPHILA MELANOGASTER ALZHEIMER’S DISEASE MODEL USING A BEHAVIORAL READOUT
Matt B. Mahoney1, Carol M. Singh1, Lenard T. Diggins1, Devin Keefe1, Emily Lund1, Phil O’Neil1, Eric Sigel1, Jim Symonds1, Alfred Villaluz1, Michael K. Ahlijanian1, Michael G. Palfreyman1,2, 1Vitruvean, LLC, Watertown, MA, USA; 2EnVivo Pharmaceuticals, Inc., Watertown, MA, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting the elderly, absconding with their memory and cognitive function. It has been classically characterized by severe dementia associated with amyloid plaques and neurofibrillary tangles in the CNS. Currently, there are no drugs that effectively ameliorate or abate disease progression. Objective: Vitruvean, LLC has strived to develop a Drosophila melanogaster-based behavioral screening platform for rapid discovery and validation of treatments for neurodegenerative diseases, such as Alzheimer’s,
P4-276
DIFFERENTIAL EXPRESSION OF CELL SURFACE PROTEINS IN HUMAN BONE MARROW MESENCHYMAL STEM CELLS CULTURED WITH OR WITHOUT BASIC FIBROBLAST GROWTH FACTOR CONTAINING MEDIUM
Sang Kwang Lee1, Youngtae Kim1, Sung-Soo Kim2, Jeong Hwa Lee1, Kun Cho1, Sang Sook Lee1, Zee-Won Lee1, Kyung-Hoon Kwon1, Young Hye Kim1, Haeyoung Suh-Kim3, Jong Shin Yoo1,4, Young Mok Park1,4, 1Korea Basic Science Istitute, Daejeon, Republic of Korea; 2Ajou University, Suwon, Republic of Korea; 3Ajou University, Suwon, Republic of Korea; 4Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, Republic of Korea. Contact e-mail: [email protected] Background: Mesenchymal stem cells (MSCs) are multipotent cells, which have the capability to differentiate into various mesenchymal tissues such as bone, cartilage, fat, tendon, muscle, neurons and astrocytes. Mesenchymal stem cells (MSCs) transplanted at sites of nerve injury are thought to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. However, they tend to lose capability of multi-lineage differentiation after several passages. It is known that basic fibroblast growth factor (bFGF) increases growth rate, differentiation potential and morphological changes of MSCs in vitro. Objective: In this report, we have used two-dimensional electrophoresis (2-DE) coupled to mass spectrometry to identify differentially expressed proteins at the cell membrane level in MSCs growing in bFGF containing medium. Methods: The cell surface proteins isolated by the biotin-avidin affinity column were separated by 2-DE in triplicate experiments. A total of 15 differentially expressed proteins were identified by quadrupole-time of flight tandem mass spectrometry. Conclusion: Nine of the proteins were up-regulated and six proteins were down-regulated in the MSCs cultured with bFGF containing medium. The expression level of three actin-related proteins, F-actin-capping protein subunit alpha-1 (CAPZA1), actin-related protein 2/3 complex subunit 2 (ARPC2), and myosin regulatory light chain 2 (MRLC2), was confirmed by Western blot analysis. The results indicate that the expression levels of CAPZA1, ARPC2, and MRLC2 are important in bFGF-induced morphological change of MSCs. P4-277
GRAPH THEORY METRICS OF RESTING STATE NETWORKS IN MCI AND AD
Kelvin O. Lim1,2, Laura S. Hemmy1,2, Bryon A. Mueller1, Chris Bell1, Sue J. Rottunda2, Michael A. Kuskowski1,2, John R. McCarten1,2, 1University of Minnesota, Minneapolis, MN, USA; 2Veterans Affairs Medical Center, Minneapolis, MN, USA. Contact e-mail: [email protected] Background: Graph Theory provides a powerful tool for analyzing complex networks derived from resting fMRI. In recent work, graph theory has been successfully applied to differentiating networks of Alzheimer’s patients and healthy controls (Supekar et al., PLOS Computational Biology, 2008). Objective: In this preliminary study, we sought to determine if differences between AD subjects and MCI subjects could be detected using graph theory network analysis. Methods: Clinical data was obtained from the work-up of 41 subjects diagnosed with probable Alzheimer’s disease (AD; DSMIV/NINCDS-ADRDA criteria) and 16 subjects with Mild Cognitive Impairment (MCI; Peterson, 2006) presenting to a VA Medical Center Memory Loss Clinic. Diagnoses were determined through a systematic consensus diagnosis process based upon a standardized history, neurological exam, neuropsychological evaluation, occupational therapy evaluation, labs, and
e11
MRI protocol. Consensus was obtained from a neurologist, geropsychiatrist, internist, and neuropsychologist. Resting fMRI data was collected on a 1.5T system with TR¼2sec for 6minutes. Preprocessing was performed including registration and slice-time adjustment. Time courses were extracted from ninety regions sing an anatomical atlas and a wavelet analysis was applied to compute frequency dependent correlation matrices. The small-world metrics characteristic path length and clustering coefficient were computed for the frequency interval 0.12-0.06Hz averaged over a threshold range representing .1 to .3 of the maximum possible number of edges in the graph. Conclusion: Subjects were 93% male and aged an average of 77.83 (6.70 SD) years. Imaging was performed an average of 40.4 (MMSE; 29.2 SD) and 59.84 (neuropsychological tests; 58.1 SD) days difference from the clinical outcomes. No group differences were found for either graph metric. No associations were found between graph metrics and age or MMSE. It may be that these metrics have more potential as early indicators of pathology than in clinical staging and that our sample is too impaired. Future investigations should contrast MCI and normal samples. Limitations of this preliminary study include the small number of subjects and mostly male sample.
P4-278
THE ABETA OLIGOMER SELECTIVE ANTIBODY NAB61 RECOGNIZES ABETA OLIGOMERS IN THE AD AND APP TRANSGENIC MOUSE BRAINS AND NEUTRALIZES ABETA MEDIATED SYNAPTIC DYSFUNCTION
Johan Lundkvist1, Leo M. Kim2, Elin Gustafsson1, Elin Hagstro¨m1, Henrik Zetterberg3, Eric Hanse3, Gabriel Von Euler1, Sergey Leonov1, Jan Na¨slund1, Camilla Dahlqvist1, John Q. Trojanowski2, Virginia M.-Y. Lee2, 1 AstraZeneca, So¨derta¨lje, Sweden; 2University of Pennsylvania, Philadelphia, PA, USA; 3Go¨teborgs Universitet, Go¨teborg, Sweden. Contact e-mail: johan. [email protected] Background: Loss of synapses is a central neuroanatomical hallmark in Alzheimer’s disease (AD). A growing body of data suggests that soluble oligomeric forms rather than fibrillar deposits of Ab, comprise the primary synaptotoxic entity of Ab. Major support for this hypothesis comes from APP transgenic mice, which display behavioural deficits prior to plaque appearance. Administration of Nab61, a monoclonal antibody selective for oligomeric forms of Ab, attenuates behavioural deficits in TG2576 mice, suggesting that Ab oligomers indeed mediate synaptic dysfunction. Objective: To further explore the role of Ab oligomers in AD. Methods: In this study we have used Nab61 as a molecular tool to explore the presence of Ab oligomers in the AD brain, in TG2576 mice and as modulators of synaptic activity in cell culture models. Conclusion: We show that Ab oligomers, mainly composed of Ab42, are elevated both in the AD and TG2576 brains. Moreover, Nab61 prevents Ab -dendrite interactions and neutralizes Ab induced changes in spine morphology and synaptic plasticity. Combined these data provide support to the hypothesis that Ab oligomers contribute to the synaptic loss associated with AD. P4-279
COMPOUND SCREENING IN A DROSOPHILA MELANOGASTER ALZHEIMER’S DISEASE MODEL USING A BEHAVIORAL READOUT
Matt B. Mahoney1, Carol M. Singh1, Lenard T. Diggins1, Devin Keefe1, Emily Lund1, Phil O’Neil1, Eric Sigel1, Jim Symonds1, Alfred Villaluz1, Michael K. Ahlijanian1, Michael G. Palfreyman1,2, 1Vitruvean, LLC, Watertown, MA, USA; 2EnVivo Pharmaceuticals, Inc., Watertown, MA, USA. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease affecting the elderly, absconding with their memory and cognitive function. It has been classically characterized by severe dementia associated with amyloid plaques and neurofibrillary tangles in the CNS. Currently, there are no drugs that effectively ameliorate or abate disease progression. Objective: Vitruvean, LLC has strived to develop a Drosophila melanogaster-based behavioral screening platform for rapid discovery and validation of treatments for neurodegenerative diseases, such as Alzheimer’s,