- Email: [email protected]
MAGNESIUM PREVENTS COGNITIVE DEFICITS AND SYNAPTIC LOSS IN STREPTOZOTOCIN-INDUCED SPORADIC AD
Poster Presentations: P2 detected by immunoprecipitation and double-labeling immunofluorescence. Results: Aß oligomer, PrP c, Fyn, NMDA receptor, GSK3ß, and phosphorylated tau were detected in lipid rafts of doubleTg mice. Aß oligomer-PrP c complex accumulated in lipid rafts. According with Aß oligomer accumulation, fyn, phosphorylated NMDA receptor, phosphorylated tau, and GSK3ß increased in lipid rafts of double Tg mice compared to that of single tau Tg mice. Conclusions: These findings suggest that Aß oligomer-PrP c complex may induce Fyn, and phosphorylation of both NMDA receptor and tau in lipid rafts leading to neurodegeneration.
P2-042
MAGNESIUM PREVENTS COGNITIVE DEFICITS AND SYNAPTIC LOSS IN STREPTOZOTOCININDUCED SPORADIC AD
Xu Zhipeng, Huazhong University of Science and Technology, Wuhan China. Contact e-mail: [email protected] Background: AD and T2DM are the most common degenerative diseases. Research has shown some common risk factors between T2DM and AD: higher cholesterol, dis-metabolism, degeneration, myloidb(Ab) deposition, Glycogen synthesis kinase 3(GSK-3), tau protein phosphorylation, oxidative stress, inflammation, ApoE4, apoptosis etc.In clinical research, magnesium levels were decreased in various tissues including brain of AD and DM patients. Magnesium ion can modulate the function of NMDA receptors and become a key regulator of synaptic plasticity. The exact role of magnesium in the neurodegenerative process of AD and DM remains elusive. Methods: Lateral ventricle injection of STZ, Atomic Absorption Spectrometr, Morris water maze, LTP, Golgi’s stain, Immunohistochemistry and Western blot were used. Results: Magnesium (MgSO4,100mg/kg*7days) treatment reduced Tau phosphorylation and prevented synapse loss and memory decline in ICV-STZ mice. In the ICV-STZ mice, the PI3K/Akt/GSK-3(S9) signaling was downregulated, whereas Mg treatment prevented the impairment of these signaling pathways, enhenced LTP, stabilized dendrites function, increased synapse transmitter, and reduced tau phosphorylation. Conclusions: Our results suggest that magnesium treatment pays an importmant rolr in synaptoprotective effects in a mouse model of SAD and may have therapeutic potential for treating AD in humans.
P2-043
APOMORPHINE THERAPY FOR NEURONAL INSULIN RESISTANCE IN ALZHEIMER’S MICE
Yasumasa Ohyagi1, Norimichi Nakamura1, Yuki Yanagihara1, Kyoko Iinuma1, Jun-ichi Kira2, 1Kyushu University, Fukuoka City, Japan; 2 Kyushu University, Fukuoka, Japan. Contact e-mail: [email protected]. kyushu-u.ac.jp Background: Diabetes mellitus (DM) is associated with the mechanism underlying Alzheimer’s disease (AD). Recently, we have reported that
P485
injection of apomorphine (APO), a dopamine receptor agonist, promotes degradation of intraneuronal A b42 via activation of insulin-degrading enzyme (IDE) and improves memory function of an AD mouse model, the triple transgenic (3xTg-AD) mice (Himeno et al, Ann Neurol, 2011). Further, we have studied neuronal insulin resistance, IDE levels, A b, hyper-phosphorylated tau protein (p-tau) and APO effects on them in 6- and 12-month-old 3xTg-AD mice. Methods: 3xTg-AD mice with three gene mutations (KM670/671NL-APP, M146V-PS1, P301L-TAU) develop memory impairment and intraneuronal A b42 accumulation around 4 months of age. Apokyn (AKN), an APO drug for Parkinson’s disease, was subcutaneously injected to 3xTg-AD mice once a week for 1 month from 6 months of age (0, 1, 5 mg/kg, n¼8) or from 12 months of age (0, 5 mg/kg, n¼10). Memory function was evaluated by Morris water maze before and after treatment. To assess insulin resistance, brain tissues were analyzed by western blotting (WB) and immunohistochemistry (IHC) using antibodies against phosphorylated (pS616,pS636+639) and total insulin receptor substrate-1 (IRS-1). Also, IDE, A band p-tau were analyzed by WB and IHC, and IDE activity was measured using the specific substrate. Results: AKN injections significantly improved memory functions of both 6- and 12-monthold 3xTg-AD mice. In WB, levels of phosphorylated IRS-1 relative to total IRS-1 were significantly decreased in AKN-treated mice, indicating an improvement in insulin resistance, while IDE protein levels and activity were significantly increased in AKN-treated mice (Fig. 1). The effects of AKN treatment were more apparent in 12-month-old than in 6-month-old mice. IHC revealed increased immunoreactivity for IDE and decreased immunoreactivity for phosphorylated IRS-1, A band p-tau in neurons in 12-month-old AKN-treated mice. Conclusions: It has recently been suggested that neuronal insulin resistance is increased and IDE is down-regulated in AD brain. Thus, some anti-DM drugs, such as nasal insulin administration and thiazolidine, were reported to be beneficial for AD. We here suggest that APO treatment is a unique therapeutic strategy specifically targeting neuronal insulin resistance up-regulating IDE in AD brain.
P2-044
THE EFFECT OF Na-GLUTAMATE TREATMENT ON BIOELECTRIC ACTIVITY AND METABOLISM IN AGING RAT BRAIN
Cristian Romeo Revnic1, Floarea Revnic2, Gabriel Ovidiu3, Catalina Pena4, Bogdan Paltineanu5, 1UMF "Carol Davila", Bucharest, Romania; 2NIGG, Bucharest, Romania; 3Affiliation not available; 4INGG Ana Aslan, Bucharest, Romania; 5UMF Tg Mures, Tg Mures, Romania. Contact e-mail: [email protected] Background: Na-Glutamate (Glu) is present in (CNS) in high concentrations and it has been suspected of causing neurodegenerative disorders, including human diseases like Huntington‘s and Alzheimer‘s disease, etc. Aim: This paper describes the effect of in vivo and in vitro Glu treatment on rat bioelectric activity in hypothalamus (HT) and cerebral cortex (C), as well as the measurement of brain enzyme activities involved in metabolism and transport of Glu in brain cells. Methods: 14 male Wistar rats, aged 24 months old, divided in two groups of 7 rats each: group A (control) was treated with 0.2 ml saline solution for two weeks, every other day, injected into lateral HT being relatively poor in Glu, which presents important connections with limbic system, reticulate mesencephalic formation and neocortex. Group B (7 rats) was treated with 0.5 mmole Glu in 0.2 ml volume for two weeks. The effect of Glu on brain enzyme activities: Mg(Na, K)-ATPase (ASAT), (ALAT) and , gGT has been investigated, also bioelectric activity in HT and neocortex was observed continuously during the experiment. Results: Glu induced an accelerated tendency of discharge frequency 10 min after injection, at cortical site (neuronal activation, respectively) followed by an inhibition of bioelectric activity. The acceleration of discharge frequency of waves (activating type)
P2-042
MAGNESIUM PREVENTS COGNITIVE DEFICITS AND SYNAPTIC LOSS IN STREPTOZOTOCININDUCED SPORADIC AD
Xu Zhipeng, Huazhong University of Science and Technology, Wuhan China. Contact e-mail: [email protected] Background: AD and T2DM are the most common degenerative diseases. Research has shown some common risk factors between T2DM and AD: higher cholesterol, dis-metabolism, degeneration, myloidb(Ab) deposition, Glycogen synthesis kinase 3(GSK-3), tau protein phosphorylation, oxidative stress, inflammation, ApoE4, apoptosis etc.In clinical research, magnesium levels were decreased in various tissues including brain of AD and DM patients. Magnesium ion can modulate the function of NMDA receptors and become a key regulator of synaptic plasticity. The exact role of magnesium in the neurodegenerative process of AD and DM remains elusive. Methods: Lateral ventricle injection of STZ, Atomic Absorption Spectrometr, Morris water maze, LTP, Golgi’s stain, Immunohistochemistry and Western blot were used. Results: Magnesium (MgSO4,100mg/kg*7days) treatment reduced Tau phosphorylation and prevented synapse loss and memory decline in ICV-STZ mice. In the ICV-STZ mice, the PI3K/Akt/GSK-3(S9) signaling was downregulated, whereas Mg treatment prevented the impairment of these signaling pathways, enhenced LTP, stabilized dendrites function, increased synapse transmitter, and reduced tau phosphorylation. Conclusions: Our results suggest that magnesium treatment pays an importmant rolr in synaptoprotective effects in a mouse model of SAD and may have therapeutic potential for treating AD in humans.
P2-043
APOMORPHINE THERAPY FOR NEURONAL INSULIN RESISTANCE IN ALZHEIMER’S MICE
Yasumasa Ohyagi1, Norimichi Nakamura1, Yuki Yanagihara1, Kyoko Iinuma1, Jun-ichi Kira2, 1Kyushu University, Fukuoka City, Japan; 2 Kyushu University, Fukuoka, Japan. Contact e-mail: [email protected]. kyushu-u.ac.jp Background: Diabetes mellitus (DM) is associated with the mechanism underlying Alzheimer’s disease (AD). Recently, we have reported that
P485
injection of apomorphine (APO), a dopamine receptor agonist, promotes degradation of intraneuronal A b42 via activation of insulin-degrading enzyme (IDE) and improves memory function of an AD mouse model, the triple transgenic (3xTg-AD) mice (Himeno et al, Ann Neurol, 2011). Further, we have studied neuronal insulin resistance, IDE levels, A b, hyper-phosphorylated tau protein (p-tau) and APO effects on them in 6- and 12-month-old 3xTg-AD mice. Methods: 3xTg-AD mice with three gene mutations (KM670/671NL-APP, M146V-PS1, P301L-TAU) develop memory impairment and intraneuronal A b42 accumulation around 4 months of age. Apokyn (AKN), an APO drug for Parkinson’s disease, was subcutaneously injected to 3xTg-AD mice once a week for 1 month from 6 months of age (0, 1, 5 mg/kg, n¼8) or from 12 months of age (0, 5 mg/kg, n¼10). Memory function was evaluated by Morris water maze before and after treatment. To assess insulin resistance, brain tissues were analyzed by western blotting (WB) and immunohistochemistry (IHC) using antibodies against phosphorylated (pS616,pS636+639) and total insulin receptor substrate-1 (IRS-1). Also, IDE, A band p-tau were analyzed by WB and IHC, and IDE activity was measured using the specific substrate. Results: AKN injections significantly improved memory functions of both 6- and 12-monthold 3xTg-AD mice. In WB, levels of phosphorylated IRS-1 relative to total IRS-1 were significantly decreased in AKN-treated mice, indicating an improvement in insulin resistance, while IDE protein levels and activity were significantly increased in AKN-treated mice (Fig. 1). The effects of AKN treatment were more apparent in 12-month-old than in 6-month-old mice. IHC revealed increased immunoreactivity for IDE and decreased immunoreactivity for phosphorylated IRS-1, A band p-tau in neurons in 12-month-old AKN-treated mice. Conclusions: It has recently been suggested that neuronal insulin resistance is increased and IDE is down-regulated in AD brain. Thus, some anti-DM drugs, such as nasal insulin administration and thiazolidine, were reported to be beneficial for AD. We here suggest that APO treatment is a unique therapeutic strategy specifically targeting neuronal insulin resistance up-regulating IDE in AD brain.
P2-044
THE EFFECT OF Na-GLUTAMATE TREATMENT ON BIOELECTRIC ACTIVITY AND METABOLISM IN AGING RAT BRAIN
Cristian Romeo Revnic1, Floarea Revnic2, Gabriel Ovidiu3, Catalina Pena4, Bogdan Paltineanu5, 1UMF "Carol Davila", Bucharest, Romania; 2NIGG, Bucharest, Romania; 3Affiliation not available; 4INGG Ana Aslan, Bucharest, Romania; 5UMF Tg Mures, Tg Mures, Romania. Contact e-mail: [email protected] Background: Na-Glutamate (Glu) is present in (CNS) in high concentrations and it has been suspected of causing neurodegenerative disorders, including human diseases like Huntington‘s and Alzheimer‘s disease, etc. Aim: This paper describes the effect of in vivo and in vitro Glu treatment on rat bioelectric activity in hypothalamus (HT) and cerebral cortex (C), as well as the measurement of brain enzyme activities involved in metabolism and transport of Glu in brain cells. Methods: 14 male Wistar rats, aged 24 months old, divided in two groups of 7 rats each: group A (control) was treated with 0.2 ml saline solution for two weeks, every other day, injected into lateral HT being relatively poor in Glu, which presents important connections with limbic system, reticulate mesencephalic formation and neocortex. Group B (7 rats) was treated with 0.5 mmole Glu in 0.2 ml volume for two weeks. The effect of Glu on brain enzyme activities: Mg(Na, K)-ATPase (ASAT), (ALAT) and , gGT has been investigated, also bioelectric activity in HT and neocortex was observed continuously during the experiment. Results: Glu induced an accelerated tendency of discharge frequency 10 min after injection, at cortical site (neuronal activation, respectively) followed by an inhibition of bioelectric activity. The acceleration of discharge frequency of waves (activating type)