- Email: [email protected]
Truncated tau transgenic mice model showing memory impairment in early age
S220
P1-158
Poster Presentations P1
CHARACTERIZATION OF THE BEHAVIOURAL DOSE-RESPONSE OF NMDA IN 3XTG-AD MICE AT DIFFERENT STAGES OF THE DISEASE AND ITS MODULATION BY EARLY-LIFE STIMULATION
Lydia Gimenez-Llort1, Ismael Alvarez-Monton1, Raquel Baeta-Corral1, Frank M. Laferla2, 1Institut de Neurociencies, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain; 2Dept. of Neurobioloy and Behaviour and Institute for Brain Aging, UCI, California Irvine, CA, USA. Contact e-mail: [email protected] Background: Glutamate excitotoxicity is considered a mechanism underlying neurodegenerative disorders and is a key target for therapeutical strategies. Transgenic mice modeling Alzheimer’s disease such as the 3xTg-AD mice allow to distinguish different succesive neuropathological stages to study the neuronal mechanisms underlying the development of the disease and to assay the outcome of preventive and/or therapeutic strategies. In the present work, we have studied the spontaneous (dopamine dependent) activity and the functional activity of glutamatergic system by means of the characterization of the biphasic motor-activity response induced by systemic administration of the glutamatergic agonist NMDA (which are know to depend on adenosine and dopamine-dependent activities). We are aimed to asses the effects of both non-excitotoxic and excitotoxic dose-ranges of NMDA and the putative differences in EC thresholds. In a second experiment we have studied the putative effects of early-life stimulation (postnatal handling) on the biphasic motor response induced by NMDA. Methods: A multicage activity system was used to record the time-course of spontaneous activity and the biphasic motor-induced effects of a wide range of doses (0, 25, 50, 100 and 200 mg/kg) of NMDA covering both non-convulsant and excitotoxic profiles. Male and female 3xTg-AD mice were studied at different ages reported to model different stages of the disease (i.e. asymptomatic: 2 month-old; early-stages of the disease: 6 month-old, with intra-neuronal beta-amyloid; advanced stages of the disease: 12 month-old, amyloid pathology and 15 month-old, amyloid and tau pathologies). Age and gendermatched non-transgenic mice were used as controls. A set of 3xTgAD and non-transgenic mice receiving early postnatal handling twice a day (PND1-PND21) were studied to assess the long-term effects of sensorial stimulation administered during the ontogeny. Results: Gender-dependent and dose-dependent effects were found both in the spontaneous and in the biphasic motor responses induced by NMDA from early stages of the disease which suggest differential functional activity of glutamatergic system in 3xTg-AD mice, as well as, the related involvement of adenosine and dopamine systems. Early-life stimulation may be able to modulate some of the motor-activity patterns. Conclusions: Glutamatergic-adenosine-dopaminergic systems are modulated in 3xTgAD mice from early stages of the disease and early-life interventions may help to ameliorate them. P1-159
TRUNCATED TAU TRANSGENIC MICE MODEL SHOWING MEMORY IMPAIRMENT IN EARLY AGE
YoungDoo Kim, Hyun Woo Choi, Hyejin Park, Yong-Keun Jung, Seoul National University, Seoul, Korea. Contact e-mail: [email protected] Background: Tau, a microtuble binding protein, is highly phosphorylated and forms an intracellular neurofibrally tangle in the brains of Alzheimer’s disease patients. Previously, we showed that Tau is cleaved by caspase 3 at the C-terminal region, Asp421, resulting in the production of ‘delta Tau’. Methods: we generated transgenic mice expressing truncated form of Tau in neuron specific promoter, BAI1-AP4. Results: truncated form of Tau was detected in the hippocampus, cortex, and cerebellum of the transgenic mice and is hyper-phosphorylated as examined with anti-phospho Tau antibodies such as PHF-1. Delta Tau transgenic mice show significant learning/spatial memory impairment from 1.5 month after birth but do not show any defect in life span (>24M) or motor function streotactic injection of Congo Red, azo-dye into i.c.v. region significantly attenuated the memory impairment of Delta Tau transgenic mice. Conclusions: These results suggest that caspase-cleaved Tau transgenic mice can be served as a model to study Tau pathology in Alzheimer’s disease.
P1-160
NEURODEGENERATION AS A CONSEQUENCE OF EXPRESSION OF ACTIVE C-ABL IN THE ADULT MOUSE BRAIN
Sarah D. Schlatterer1, Matthew A. Tremblay1, Christopher M. Acker1, Peter Davies1,2, 1Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; 2The Litwin-Zucker Center for Research on Alzheimer’s Disease, Feinstein Institute of Medical Research, North Shore/ LIJ Health Care System, Manhasset, NY, USA. Contact e-mail: smurray@ aecom.yu.edu Background: Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). In cell transfection experiments, c-Abl has been shown to phosphorylate tau on tyrosines 18 and 394, and there is evidence that both tyrosines are phosphorylated in tau accumulating in neurofibrillary tangles in AD. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis, at least in cells outside the CNS. To examine the consequences of c-abl activation in the adult brain, we have constructed transgenic mice expressing a consitutively active form of c-abl with a neuronspecific promoter (CamKII) regulated by doxicycline (Tet-Off). Methods: We perform Western blotting, immunohistochemistry, and immunoprecipitation experiments in this study. Results: Expression of active c-abl in adult mouse brain results in substantial increases in neuronal protein tyrosine phosphorylation, including increased tyrosine phosphorylation of tau. In both male and female mice, expression of active c-abl is followed by a severe neurodegeneration, especially in the CA1 region of the hippocampus. Neuronal loss occurs earlier in male mice (8-14 weeks after removal of doxicycline) than in females (10 - 18 weeks), but in both cases is accompanied by substantial microgliosis and astrocyctosis. Neurodegeneration is also evident in the striatum, and to a lesser extent in the cerebral cortex. A number of studies have defined the substrates phosphorylated by active cabl in white blood cells, but there is little information on c-abl substrates in neurons. We have used phosphotyrosine immunoprecipitation to identify proteins phosphorylated in the brains of mice expressing active c-abl, and to attempt to define the mechanism of neurodegeneration. The potential role of tau phosphorylation is being examined by crossing mice with inducible c-abl activity on to a tau knockout background. Conclusions: Given the evidence of c-abl activation in the human AD brain, it is possible that aberrant tyrosine phosphorylation of tau and other proteins drives neurodegeneration in the human disease.
P1-161
CHARACTERIZATION OF LEARNING DEFICITS IN TWO MODELS OF ALZHEIMER’S DISEASE
Amanda Wright, Raphael Zinn, Bryce Vissel, Garvan Institute, NSW Sydney, Australia. Contact e-mail: [email protected] Background: Mouse models of Alzheimer’s disease provide a powerful tool for studying mechanisms and treatments of neurological disease. Thorough analyses of these models, behaviour provides a means to assess whether therapeutic interventions designed to alter disease process will affect disease manifestation. Methods: In this study, we undertake a detailed analysis of phenotype progression in two lines of Alzheimer’s mice, the 5XFAD line, which carries the human APP(695) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) Familial Alzheimer’s Disease (FAD) mutations and human PS1 harboring two FAD mutations, and J20 line, which carries the human amyloid protein precursor bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutation. Results: We study the progression of the learning deficit in radial arm maze, fear conditioning and Y-maze, and we assess progression of anxiety phenotype in elevated plus maze and open field. We also assess neuro-anatomical correlates of the learning deficits. Conclusions: A thorough knowledge of phenotype progression in these models will assist in future studies directed to determine an optimal strategy for testing therapeutic intervention’s.
P1-158
Poster Presentations P1
CHARACTERIZATION OF THE BEHAVIOURAL DOSE-RESPONSE OF NMDA IN 3XTG-AD MICE AT DIFFERENT STAGES OF THE DISEASE AND ITS MODULATION BY EARLY-LIFE STIMULATION
Lydia Gimenez-Llort1, Ismael Alvarez-Monton1, Raquel Baeta-Corral1, Frank M. Laferla2, 1Institut de Neurociencies, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain; 2Dept. of Neurobioloy and Behaviour and Institute for Brain Aging, UCI, California Irvine, CA, USA. Contact e-mail: [email protected] Background: Glutamate excitotoxicity is considered a mechanism underlying neurodegenerative disorders and is a key target for therapeutical strategies. Transgenic mice modeling Alzheimer’s disease such as the 3xTg-AD mice allow to distinguish different succesive neuropathological stages to study the neuronal mechanisms underlying the development of the disease and to assay the outcome of preventive and/or therapeutic strategies. In the present work, we have studied the spontaneous (dopamine dependent) activity and the functional activity of glutamatergic system by means of the characterization of the biphasic motor-activity response induced by systemic administration of the glutamatergic agonist NMDA (which are know to depend on adenosine and dopamine-dependent activities). We are aimed to asses the effects of both non-excitotoxic and excitotoxic dose-ranges of NMDA and the putative differences in EC thresholds. In a second experiment we have studied the putative effects of early-life stimulation (postnatal handling) on the biphasic motor response induced by NMDA. Methods: A multicage activity system was used to record the time-course of spontaneous activity and the biphasic motor-induced effects of a wide range of doses (0, 25, 50, 100 and 200 mg/kg) of NMDA covering both non-convulsant and excitotoxic profiles. Male and female 3xTg-AD mice were studied at different ages reported to model different stages of the disease (i.e. asymptomatic: 2 month-old; early-stages of the disease: 6 month-old, with intra-neuronal beta-amyloid; advanced stages of the disease: 12 month-old, amyloid pathology and 15 month-old, amyloid and tau pathologies). Age and gendermatched non-transgenic mice were used as controls. A set of 3xTgAD and non-transgenic mice receiving early postnatal handling twice a day (PND1-PND21) were studied to assess the long-term effects of sensorial stimulation administered during the ontogeny. Results: Gender-dependent and dose-dependent effects were found both in the spontaneous and in the biphasic motor responses induced by NMDA from early stages of the disease which suggest differential functional activity of glutamatergic system in 3xTg-AD mice, as well as, the related involvement of adenosine and dopamine systems. Early-life stimulation may be able to modulate some of the motor-activity patterns. Conclusions: Glutamatergic-adenosine-dopaminergic systems are modulated in 3xTgAD mice from early stages of the disease and early-life interventions may help to ameliorate them. P1-159
TRUNCATED TAU TRANSGENIC MICE MODEL SHOWING MEMORY IMPAIRMENT IN EARLY AGE
YoungDoo Kim, Hyun Woo Choi, Hyejin Park, Yong-Keun Jung, Seoul National University, Seoul, Korea. Contact e-mail: [email protected] Background: Tau, a microtuble binding protein, is highly phosphorylated and forms an intracellular neurofibrally tangle in the brains of Alzheimer’s disease patients. Previously, we showed that Tau is cleaved by caspase 3 at the C-terminal region, Asp421, resulting in the production of ‘delta Tau’. Methods: we generated transgenic mice expressing truncated form of Tau in neuron specific promoter, BAI1-AP4. Results: truncated form of Tau was detected in the hippocampus, cortex, and cerebellum of the transgenic mice and is hyper-phosphorylated as examined with anti-phospho Tau antibodies such as PHF-1. Delta Tau transgenic mice show significant learning/spatial memory impairment from 1.5 month after birth but do not show any defect in life span (>24M) or motor function streotactic injection of Congo Red, azo-dye into i.c.v. region significantly attenuated the memory impairment of Delta Tau transgenic mice. Conclusions: These results suggest that caspase-cleaved Tau transgenic mice can be served as a model to study Tau pathology in Alzheimer’s disease.
P1-160
NEURODEGENERATION AS A CONSEQUENCE OF EXPRESSION OF ACTIVE C-ABL IN THE ADULT MOUSE BRAIN
Sarah D. Schlatterer1, Matthew A. Tremblay1, Christopher M. Acker1, Peter Davies1,2, 1Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; 2The Litwin-Zucker Center for Research on Alzheimer’s Disease, Feinstein Institute of Medical Research, North Shore/ LIJ Health Care System, Manhasset, NY, USA. Contact e-mail: smurray@ aecom.yu.edu Background: Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). In cell transfection experiments, c-Abl has been shown to phosphorylate tau on tyrosines 18 and 394, and there is evidence that both tyrosines are phosphorylated in tau accumulating in neurofibrillary tangles in AD. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis, at least in cells outside the CNS. To examine the consequences of c-abl activation in the adult brain, we have constructed transgenic mice expressing a consitutively active form of c-abl with a neuronspecific promoter (CamKII) regulated by doxicycline (Tet-Off). Methods: We perform Western blotting, immunohistochemistry, and immunoprecipitation experiments in this study. Results: Expression of active c-abl in adult mouse brain results in substantial increases in neuronal protein tyrosine phosphorylation, including increased tyrosine phosphorylation of tau. In both male and female mice, expression of active c-abl is followed by a severe neurodegeneration, especially in the CA1 region of the hippocampus. Neuronal loss occurs earlier in male mice (8-14 weeks after removal of doxicycline) than in females (10 - 18 weeks), but in both cases is accompanied by substantial microgliosis and astrocyctosis. Neurodegeneration is also evident in the striatum, and to a lesser extent in the cerebral cortex. A number of studies have defined the substrates phosphorylated by active cabl in white blood cells, but there is little information on c-abl substrates in neurons. We have used phosphotyrosine immunoprecipitation to identify proteins phosphorylated in the brains of mice expressing active c-abl, and to attempt to define the mechanism of neurodegeneration. The potential role of tau phosphorylation is being examined by crossing mice with inducible c-abl activity on to a tau knockout background. Conclusions: Given the evidence of c-abl activation in the human AD brain, it is possible that aberrant tyrosine phosphorylation of tau and other proteins drives neurodegeneration in the human disease.
P1-161
CHARACTERIZATION OF LEARNING DEFICITS IN TWO MODELS OF ALZHEIMER’S DISEASE
Amanda Wright, Raphael Zinn, Bryce Vissel, Garvan Institute, NSW Sydney, Australia. Contact e-mail: [email protected] Background: Mouse models of Alzheimer’s disease provide a powerful tool for studying mechanisms and treatments of neurological disease. Thorough analyses of these models, behaviour provides a means to assess whether therapeutic interventions designed to alter disease process will affect disease manifestation. Methods: In this study, we undertake a detailed analysis of phenotype progression in two lines of Alzheimer’s mice, the 5XFAD line, which carries the human APP(695) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) Familial Alzheimer’s Disease (FAD) mutations and human PS1 harboring two FAD mutations, and J20 line, which carries the human amyloid protein precursor bearing both the Swedish (K670N/M671L) and the Indiana (V717F) mutation. Results: We study the progression of the learning deficit in radial arm maze, fear conditioning and Y-maze, and we assess progression of anxiety phenotype in elevated plus maze and open field. We also assess neuro-anatomical correlates of the learning deficits. Conclusions: A thorough knowledge of phenotype progression in these models will assist in future studies directed to determine an optimal strategy for testing therapeutic intervention’s.