- Email: [email protected]
PS1 MOUSE MODEL OF ALZHEIMER’S DISEASE
Poster Presentations: Wednesday, July 27, 2016
significant increase in fMRI activation patterns during passive listening to familiar and unfamiliar music in AD patients. Our saw increased brain activity in parts of the Inferior Frontal Gyrus, Middle Temporal Gyrus, Parahippocampa Gyrus, Parahippocampal, Parietal Lobe, Superior Temporal Gyrus, Middle Temporal Gyrus, Dorsal Posterior Cingulate Cortex, Anterior Temporal Lobe and Angular Gyrus while listening to unfamiliar music. Familiar music shows increased brain activity in parts of the Insula, Middle Temporal Gyrus, Parahippocampa Gyrus and Superior Temporal Gyrus. Conclusions: AD patients showed increased brain activation while listening to familiar and unfamiliar melodies after the MT intervention. We confirmed that the activation pattern of the brain during the processing of familiar and unfamiliar music was different in AD patients after MT intervention.
P4-043
BEHAVIOURAL PHENOTYPING OF ALZHEIMER’S DISEASE MODEL MICE: UNDERSTANDING MOUSE MODELS OF ALZHEIMER’S DISEASE
Richard E. Brown, Dalhousie University, Halifax, NS, Canada. Contact e-mail: [email protected] Background: Although transgenic mice have been developed as models of Alzheimer’s Disease, the behavioural phenotypes of these mice are often quite surprizing. Some behaviours in these mice show age-related deficits while others appear normal. Some deficits are more likely to appear in one sex and not the other. The only way to determine the age-related changes in these mouse models is to conduct lifespan behavioural phenotyping using behavioural bioassays. Methods: We have examined the sensory, motor and cognitive performance of both males and females of a number of Alzheimer model mice and their wildtype controls over their lifespan. We examined age-related changes in spatial learning and memory, procedural learning and memory, and olfactory memory in male and female APP/PSEN1 double transgenic, 3x-Tg AD and 5XFAD mouse models of AD and their appropriate control strains between 3 and 18 months of age. The data examines sex differences, sex by genotype and sex by age interactions in each memory system. We also examine sex differences in longevity of each genotype. Results: We found sex differences in a number of learning and memory tasks. There were no genotype or agerelated deficits in olfactory memory. The 5xFAD mice had agerelated deficits in procedural learning. There were also age-and genotype-related deficits in visuo-spatial memory. Confounding effects of background strain, behavioural measures and housing conditions will be discussed. Conclusions: Each mouse model of AD has different behavioural phenotypes and there are age and sex differences in the degree of behavioural dysfunction, thus behavioural phenotyping of both sexes of each mouse model is essential.
P4-044
DIFFERENCES IN OLFACTORY DETECTION AND RESPONSE BIAS IN THE 3XTG-AD AND 5XFAD MOUSE MODELS OF ALZHEIMER’S DISEASE
Kyle M. Roddick, Heather M. Schellinck, Richard E. Brown, Dalhousie University, Halifax, NS, Canada. Contact e-mail: [email protected] Background: Olfactory dysfunction has been identified as a symp-
tom of Alzheimer’s disease (AD) that appears prior to more
P1031
severe cognitive impairments, and has been proposed as a possible method of early diagnosis. The 3xTg-AD mouse model of AD develops amyloid and tau pathology due to mutations to amyloid precursor protein, presenilin 1, and tau, while the 5XFAD mouse model develops amyloid but not tau pathology due to three mutations to amyloid precursor protein and two mutations to presenilin 1. We investigated these two commonly used mouse models for changes in olfactory function. Methods: Female and male 3xTg-AD mice and 5XFAD mice, and their wildtype controls, were tested at six months of age using an automated olfactometer. Mice were presented with decreasing concentrations of ethyl acetate on a go no-go odour detection task. Results: Female 3xTg-AD mice had decreased detection of the odour compared to their wildtype controls and showed a more liberal response bias. There was no difference between male 3xTg-AD mice and their wildtype controls. 5XFAD mice did not differ from their wildtype controls on odour detection, but did show a less liberal response bias. There was also a sex difference in the 5xFAD model and their wildtype controls, with the female mice displaying greater detection than male mice, and a less liberal response bias than the males. Conclusions: Olfactory detection appears to be impaired in female 3xTg-AD mice, but not in male 3xTg-AD mice. No such impairment is seen in the either sex of the 5XFAD mice, though female 5XFAD mice did perform better than male 5XFAD mice. The changes in response bias seen in the female 3xTg-AD and 5XFAD mice of both sexes suggests there are alterations in cognitive function of both model that affected performance on this task.
P4-045
EVALUATION OF CIRCADIAN RHYTHMS AND SLEEP IN THE APP/PS1 MOUSE MODEL OF ALZHEIMER’S DISEASE
Brianne A. Kent1, Mateusz Michalik2, Howard H. Feldman1, Ralph E. Mistlberger2, Haakon B. Nygaard1, 1University of British Columbia, Vancouver, BC, Canada; 2Simon Fraser University, Burnaby, BC, Canada. Contact e-mail: [email protected] Background: It is well documented that patients with Alzheimer’s
disease (AD) experience disrupted circadian rhythms and sleep. An estimated 60% of community-dwelling AD patients experience insomnia or other sleep disturbances (Guarnieri et al., 2012), which are highly disruptive, stressful, and a leading cause of patients requiring institutional care (Bianchetti et al., 1995). It is largely assumed that in AD, the disruption of circadian rhythms is caused by the dampening of central SCN-driven rhythms; however, there is some evidence that disruption could be due to the uncoupling of central and peripheral rhythms (Chen et al., 2014, Cermakian et al., 2011). Methods: The objective was to provide a detailed description of sleep and circadian rhythms in the APP/PS1 mouse model (APPswe/PSEN1dE9) and to identify whether central and peripheral circadian rhythms are misaligned. Once a phenotype was identified, the goal was to evaluate pharmacological and behavioural interventions to improve sleep and circadian synchrony. To evaluate circadian rhythmicity, mice were housed in temporal isolation chambers (LD 12:12) for continuous recording using infrared motion sensors monitored using Clocklab (Actimetrics). A variety of LD schedules and food restriction were used to help provide estimates of activity level, pacemaker amplitude, light sensitivity, endogenous period of the
P1032
Poster Presentations: Wednesday, July 27, 2016
central oscillator, oscillator response to light pulse, and speed of entrainment to light and mealtime. To evaluate sleep, mice received cranial implants of a modular EEG/EMG electrode grid (Pinnacle Systems). This allowed both rapid eye movement (REM) and non-REM phases to be monitored. We were particularly interested in slow wave sleep (i.e., Phase 3 of non-REM), which is essential for clearing misfolded proteins contributing to AD pathogenesis (e.g., amyloid-beta; Ab), suggesting a bidirectional relationship between sleep and AD pathology (Xie et al., 2013; Ju et al., 2014). Results: Sleep and circadian rhythm data collection is ongoing and will be collected at 6, 9, and 12 months of age. Behavioural analysis will be followed by probing the molecular processes underlying the circadian phenotype. Conclusions: The APP/PS1 mouse model of AD may be a useful model for developing interventions to improve sleep and circadian synchrony.
P4-046
IMPACT OF PRENATAL ZINC SUPPLEMENTATION ON NEUROCHEMICAL, BIOCHEMICAL AND COGNITIVE DEFICITS PRODUCED IN INFANTS OF LPS-INFECTED FEMALE RATS
Neha Sharma, Palvi Arora, Bimla Nehru, Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: Recent research revealed an association between maternal infection i. e LPS exposure during pregnancy and increased risk for CNS disorder in offsprings. The environment insults during pregnancy affects rat brain development and exerts alterations in behavior, metabolism and health of offspring. Especially, maternal infections occurring during the third trimester of pregnancy interfere with the fundamental neurodevelopment events – cell proliferation and migration. Zinc supplementation however, has been shown to prevent endotoxin [lipopolysaccharide (LPS)]-induced teratogenicity and lipopolysaccharideinduced fetal growth restriction and demise through its anti-inflammatory properties by regulating TNF-a and interleukin (IL)–1b, NMDAR activity. The efficacy of zinc in ameliorating neurodegenerative effects caused in pups of LPS infected mothers has been least explored. Therefore, the purpose of this study is to investigate the effects of Zinc sulfate on the rat brain development exposed to endotoxemia during third trimester of pregnancy. Gender dependent behavioral, biochemical, histological and neurochemical effects induced by endotoxemia during third trimester of pregnancy were studied in developing rat brains Methods: Pregnant female rats were administered single dose of LPS (200mg/kg b.wt, i.p.) during third trimester of their pregnancy. Zinc supplementation was given through drinking water (75mg ZnSO4/liter deionized water) throughout pregnancy. Results: Following LPS injection in pregnant female rats, significantly altered levels of neurotransmitters and associated motor behavior dysfunction as well as cognitive decline have been observed in male as well as female pups. Whereas, supplementation with Zinc limited the alterations in behavioral parameters (Active passive avoidance, plus maze, 8 arm radial maze, actophotometer and rotarod) as well as significantly improved the level of neurotransmitters in prenatally exposed pups of both genders. However, antioxidant defence system was found to be excessively compromised in prenatally exposed female pups when compare to LPS treated
male pups as well as control pups. Conclusions: Hence, the study indicated LPS mediated toxicity in prenatally exposed rats are gender specific and supplementation during infection to LPS in pregnancy mitigated LPS-induced alterations.
P4-047
RESVERATROL ATTENUATES INSULIN RESISTANCE–ASSOCIATED COGNITIVE DEFICITS IN RATS
Anand Kamal Sachdeva, Kanwaljit Chopra, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: A large body of evidence now suggests that Alz-
heimer’s is primarily a metabolic disease, which is characterized by glucose intolerance and CNS insulin resistance. It is accompanied by decreased expression of insulin, insulin receptor genes and impaired brain insulin signaling. Resveratrol is a natural polyphenol widely present in plants which has demonstrated neuroprotective effects in various preclinical and clinical studies. Thus, the present study was designed to elucidate the neuroprotective effect of resveratrol in an experimental paradigm of insulin resistanceinduced cognitive deficits in rats. Methods: Six-week-old male Wistar rats were fed with 15% fructose in drinking water for 24 weeks. Body mass, food and water intakes were measured regularly as well as plasma insulin, blood glucose, glycosylated heamoglobin, HOMA-IR, lipid levels and blood pressure were measured to ensure development of insulin resistance. Insulin resistance associated cognitive impairment was measured by using Morris water maze test (computer tracking using EthoVision software) and elevated plus maze on 24th week. Treatment with resveratrol (5, 10 and 20 mg/kg) was initiated after 6th week of fructose administration and continued till the end of study. Results: Insulin resistance was evident at 6th week and persisted till end of study (24th week) as demonstrated by significant increase in body weight, plasma insulin, blood glucose, glycosylated heamoglobin, HOMA-IR, blood pressure and a deranged lipid profile. Cognitive deficit was significantly evident at 24th week. Fructose-induced neuronal deficits were coupled with significant alterations in oxidative-nitrodative stress along with elevation of NF-kB and its downstream mediators as TNF-a, TGF-b1, caspase-3 and IL 1b levels. Resveratrol dosedependently ameliorated emergence of insulin resistance-induced memory impairment along with mitigation of oxido-nitrosative stress mediated alterations in cytokine levels. Conclusions: These results provide a novel insight into the neuroprotective effects of resveratrol and its possible therapeutic role in neuronal insulin resistance-induced memory impairment.
P4-048
CONVERGENT ANALYSIS OF ENDOPHENOTYPES IN PROGRESSIVE SUPRANUCLEAR PALSY
Mariet Allen1, Xue Wang1, Curtis S. Younkin1, Daniel Serie1, Zhifu Sun2, Jeremy D. Burgess1, Saurabh Baheti2, Naomi Kouri1, Thuy Nguyen1, Sarah Lincoln1, Kimberly G. Malphrus1, Minerva M. Carrasquillo1, Fanggeng Zou1, High-Seng Chai2, Melissa E. Murray1, Gerard D. Schellenberg3, Steven G. Younkin1, Julia E. Crook1, Tamas Ordog2, Yan W. Asmann1, Dennis W. Dickson1, Nilufer ErtekinTaner1, 1Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN,
significant increase in fMRI activation patterns during passive listening to familiar and unfamiliar music in AD patients. Our saw increased brain activity in parts of the Inferior Frontal Gyrus, Middle Temporal Gyrus, Parahippocampa Gyrus, Parahippocampal, Parietal Lobe, Superior Temporal Gyrus, Middle Temporal Gyrus, Dorsal Posterior Cingulate Cortex, Anterior Temporal Lobe and Angular Gyrus while listening to unfamiliar music. Familiar music shows increased brain activity in parts of the Insula, Middle Temporal Gyrus, Parahippocampa Gyrus and Superior Temporal Gyrus. Conclusions: AD patients showed increased brain activation while listening to familiar and unfamiliar melodies after the MT intervention. We confirmed that the activation pattern of the brain during the processing of familiar and unfamiliar music was different in AD patients after MT intervention.
P4-043
BEHAVIOURAL PHENOTYPING OF ALZHEIMER’S DISEASE MODEL MICE: UNDERSTANDING MOUSE MODELS OF ALZHEIMER’S DISEASE
Richard E. Brown, Dalhousie University, Halifax, NS, Canada. Contact e-mail: [email protected] Background: Although transgenic mice have been developed as models of Alzheimer’s Disease, the behavioural phenotypes of these mice are often quite surprizing. Some behaviours in these mice show age-related deficits while others appear normal. Some deficits are more likely to appear in one sex and not the other. The only way to determine the age-related changes in these mouse models is to conduct lifespan behavioural phenotyping using behavioural bioassays. Methods: We have examined the sensory, motor and cognitive performance of both males and females of a number of Alzheimer model mice and their wildtype controls over their lifespan. We examined age-related changes in spatial learning and memory, procedural learning and memory, and olfactory memory in male and female APP/PSEN1 double transgenic, 3x-Tg AD and 5XFAD mouse models of AD and their appropriate control strains between 3 and 18 months of age. The data examines sex differences, sex by genotype and sex by age interactions in each memory system. We also examine sex differences in longevity of each genotype. Results: We found sex differences in a number of learning and memory tasks. There were no genotype or agerelated deficits in olfactory memory. The 5xFAD mice had agerelated deficits in procedural learning. There were also age-and genotype-related deficits in visuo-spatial memory. Confounding effects of background strain, behavioural measures and housing conditions will be discussed. Conclusions: Each mouse model of AD has different behavioural phenotypes and there are age and sex differences in the degree of behavioural dysfunction, thus behavioural phenotyping of both sexes of each mouse model is essential.
P4-044
DIFFERENCES IN OLFACTORY DETECTION AND RESPONSE BIAS IN THE 3XTG-AD AND 5XFAD MOUSE MODELS OF ALZHEIMER’S DISEASE
Kyle M. Roddick, Heather M. Schellinck, Richard E. Brown, Dalhousie University, Halifax, NS, Canada. Contact e-mail: [email protected] Background: Olfactory dysfunction has been identified as a symp-
tom of Alzheimer’s disease (AD) that appears prior to more
P1031
severe cognitive impairments, and has been proposed as a possible method of early diagnosis. The 3xTg-AD mouse model of AD develops amyloid and tau pathology due to mutations to amyloid precursor protein, presenilin 1, and tau, while the 5XFAD mouse model develops amyloid but not tau pathology due to three mutations to amyloid precursor protein and two mutations to presenilin 1. We investigated these two commonly used mouse models for changes in olfactory function. Methods: Female and male 3xTg-AD mice and 5XFAD mice, and their wildtype controls, were tested at six months of age using an automated olfactometer. Mice were presented with decreasing concentrations of ethyl acetate on a go no-go odour detection task. Results: Female 3xTg-AD mice had decreased detection of the odour compared to their wildtype controls and showed a more liberal response bias. There was no difference between male 3xTg-AD mice and their wildtype controls. 5XFAD mice did not differ from their wildtype controls on odour detection, but did show a less liberal response bias. There was also a sex difference in the 5xFAD model and their wildtype controls, with the female mice displaying greater detection than male mice, and a less liberal response bias than the males. Conclusions: Olfactory detection appears to be impaired in female 3xTg-AD mice, but not in male 3xTg-AD mice. No such impairment is seen in the either sex of the 5XFAD mice, though female 5XFAD mice did perform better than male 5XFAD mice. The changes in response bias seen in the female 3xTg-AD and 5XFAD mice of both sexes suggests there are alterations in cognitive function of both model that affected performance on this task.
P4-045
EVALUATION OF CIRCADIAN RHYTHMS AND SLEEP IN THE APP/PS1 MOUSE MODEL OF ALZHEIMER’S DISEASE
Brianne A. Kent1, Mateusz Michalik2, Howard H. Feldman1, Ralph E. Mistlberger2, Haakon B. Nygaard1, 1University of British Columbia, Vancouver, BC, Canada; 2Simon Fraser University, Burnaby, BC, Canada. Contact e-mail: [email protected] Background: It is well documented that patients with Alzheimer’s
disease (AD) experience disrupted circadian rhythms and sleep. An estimated 60% of community-dwelling AD patients experience insomnia or other sleep disturbances (Guarnieri et al., 2012), which are highly disruptive, stressful, and a leading cause of patients requiring institutional care (Bianchetti et al., 1995). It is largely assumed that in AD, the disruption of circadian rhythms is caused by the dampening of central SCN-driven rhythms; however, there is some evidence that disruption could be due to the uncoupling of central and peripheral rhythms (Chen et al., 2014, Cermakian et al., 2011). Methods: The objective was to provide a detailed description of sleep and circadian rhythms in the APP/PS1 mouse model (APPswe/PSEN1dE9) and to identify whether central and peripheral circadian rhythms are misaligned. Once a phenotype was identified, the goal was to evaluate pharmacological and behavioural interventions to improve sleep and circadian synchrony. To evaluate circadian rhythmicity, mice were housed in temporal isolation chambers (LD 12:12) for continuous recording using infrared motion sensors monitored using Clocklab (Actimetrics). A variety of LD schedules and food restriction were used to help provide estimates of activity level, pacemaker amplitude, light sensitivity, endogenous period of the
P1032
Poster Presentations: Wednesday, July 27, 2016
central oscillator, oscillator response to light pulse, and speed of entrainment to light and mealtime. To evaluate sleep, mice received cranial implants of a modular EEG/EMG electrode grid (Pinnacle Systems). This allowed both rapid eye movement (REM) and non-REM phases to be monitored. We were particularly interested in slow wave sleep (i.e., Phase 3 of non-REM), which is essential for clearing misfolded proteins contributing to AD pathogenesis (e.g., amyloid-beta; Ab), suggesting a bidirectional relationship between sleep and AD pathology (Xie et al., 2013; Ju et al., 2014). Results: Sleep and circadian rhythm data collection is ongoing and will be collected at 6, 9, and 12 months of age. Behavioural analysis will be followed by probing the molecular processes underlying the circadian phenotype. Conclusions: The APP/PS1 mouse model of AD may be a useful model for developing interventions to improve sleep and circadian synchrony.
P4-046
IMPACT OF PRENATAL ZINC SUPPLEMENTATION ON NEUROCHEMICAL, BIOCHEMICAL AND COGNITIVE DEFICITS PRODUCED IN INFANTS OF LPS-INFECTED FEMALE RATS
Neha Sharma, Palvi Arora, Bimla Nehru, Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: Recent research revealed an association between maternal infection i. e LPS exposure during pregnancy and increased risk for CNS disorder in offsprings. The environment insults during pregnancy affects rat brain development and exerts alterations in behavior, metabolism and health of offspring. Especially, maternal infections occurring during the third trimester of pregnancy interfere with the fundamental neurodevelopment events – cell proliferation and migration. Zinc supplementation however, has been shown to prevent endotoxin [lipopolysaccharide (LPS)]-induced teratogenicity and lipopolysaccharideinduced fetal growth restriction and demise through its anti-inflammatory properties by regulating TNF-a and interleukin (IL)–1b, NMDAR activity. The efficacy of zinc in ameliorating neurodegenerative effects caused in pups of LPS infected mothers has been least explored. Therefore, the purpose of this study is to investigate the effects of Zinc sulfate on the rat brain development exposed to endotoxemia during third trimester of pregnancy. Gender dependent behavioral, biochemical, histological and neurochemical effects induced by endotoxemia during third trimester of pregnancy were studied in developing rat brains Methods: Pregnant female rats were administered single dose of LPS (200mg/kg b.wt, i.p.) during third trimester of their pregnancy. Zinc supplementation was given through drinking water (75mg ZnSO4/liter deionized water) throughout pregnancy. Results: Following LPS injection in pregnant female rats, significantly altered levels of neurotransmitters and associated motor behavior dysfunction as well as cognitive decline have been observed in male as well as female pups. Whereas, supplementation with Zinc limited the alterations in behavioral parameters (Active passive avoidance, plus maze, 8 arm radial maze, actophotometer and rotarod) as well as significantly improved the level of neurotransmitters in prenatally exposed pups of both genders. However, antioxidant defence system was found to be excessively compromised in prenatally exposed female pups when compare to LPS treated
male pups as well as control pups. Conclusions: Hence, the study indicated LPS mediated toxicity in prenatally exposed rats are gender specific and supplementation during infection to LPS in pregnancy mitigated LPS-induced alterations.
P4-047
RESVERATROL ATTENUATES INSULIN RESISTANCE–ASSOCIATED COGNITIVE DEFICITS IN RATS
Anand Kamal Sachdeva, Kanwaljit Chopra, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Contact e-mail: [email protected] Background: A large body of evidence now suggests that Alz-
heimer’s is primarily a metabolic disease, which is characterized by glucose intolerance and CNS insulin resistance. It is accompanied by decreased expression of insulin, insulin receptor genes and impaired brain insulin signaling. Resveratrol is a natural polyphenol widely present in plants which has demonstrated neuroprotective effects in various preclinical and clinical studies. Thus, the present study was designed to elucidate the neuroprotective effect of resveratrol in an experimental paradigm of insulin resistanceinduced cognitive deficits in rats. Methods: Six-week-old male Wistar rats were fed with 15% fructose in drinking water for 24 weeks. Body mass, food and water intakes were measured regularly as well as plasma insulin, blood glucose, glycosylated heamoglobin, HOMA-IR, lipid levels and blood pressure were measured to ensure development of insulin resistance. Insulin resistance associated cognitive impairment was measured by using Morris water maze test (computer tracking using EthoVision software) and elevated plus maze on 24th week. Treatment with resveratrol (5, 10 and 20 mg/kg) was initiated after 6th week of fructose administration and continued till the end of study. Results: Insulin resistance was evident at 6th week and persisted till end of study (24th week) as demonstrated by significant increase in body weight, plasma insulin, blood glucose, glycosylated heamoglobin, HOMA-IR, blood pressure and a deranged lipid profile. Cognitive deficit was significantly evident at 24th week. Fructose-induced neuronal deficits were coupled with significant alterations in oxidative-nitrodative stress along with elevation of NF-kB and its downstream mediators as TNF-a, TGF-b1, caspase-3 and IL 1b levels. Resveratrol dosedependently ameliorated emergence of insulin resistance-induced memory impairment along with mitigation of oxido-nitrosative stress mediated alterations in cytokine levels. Conclusions: These results provide a novel insight into the neuroprotective effects of resveratrol and its possible therapeutic role in neuronal insulin resistance-induced memory impairment.
P4-048
CONVERGENT ANALYSIS OF ENDOPHENOTYPES IN PROGRESSIVE SUPRANUCLEAR PALSY
Mariet Allen1, Xue Wang1, Curtis S. Younkin1, Daniel Serie1, Zhifu Sun2, Jeremy D. Burgess1, Saurabh Baheti2, Naomi Kouri1, Thuy Nguyen1, Sarah Lincoln1, Kimberly G. Malphrus1, Minerva M. Carrasquillo1, Fanggeng Zou1, High-Seng Chai2, Melissa E. Murray1, Gerard D. Schellenberg3, Steven G. Younkin1, Julia E. Crook1, Tamas Ordog2, Yan W. Asmann1, Dennis W. Dickson1, Nilufer ErtekinTaner1, 1Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN,