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Cognitive decline in diabetes
e304
Abstracts / Neuroscience Research 68S (2010) e223–e334
P2-n07 Alterations in microglial activation and amyloid deposits in Alzheimer’s disease Yasuomi Ouchi 1 , Masamichi Yokokura 2 , Shunsuke Yagi 1 , Mitsuru Kikuchi 3 , Etsuji Yoshikawa 4 , Masami Futatsubashi 4 , Yumi Oboshi 1 , Masanobu Sakamoto 5 , Takatoshi Ueki 6 1
Molecular Imaging Frontier Res Ctr, Hamamatsu University Med Psychiatry, Hamamatsu University Med, Hamamatsu, Japan 3 Psychiatry, Kanazawa University, Kanazawa, Japan 4 Hamamatsu Photonics KK, Hamamatsu, Japan 5 Hamamatsu Medical Center, Hamamatsu, Japan 6 Anatomy, Hamamatsu University Med, Hamamatsu, Japan
2
It is well known that amyloid  protein (A) is a major pathological substance in Alzheimer’s disease (AD). A large amount of A deposits along with activated microglia is considered detrimental to neurons in the AD brain. However, it remains unclear whether these two events are pathogenic conspirators or occurring in parallel to produce cognitive decline in AD patients. The purpose of this study was to clarify the in vivo relation between A accumulation and neuroinflammation along with cognitive decline in the living AD brain. Methods: Eleven patients with AD underwent a series of positron emission tomography (PET) measurements with [11C](R)PK11195, [11C]PIB and [18F]FDG and a battery of cognitive tests within the same day. Binding potentials (BPs) for [11C](R)PK11195 and [11C]PIB and regional uptake of [18F]FDG were calculated semi-quantitatively. Results: Significant changes in BPs of [11C](R)PK11195 and [11C]PIB were found in the well-known parietotemporal regions of AD patients. The clinicalbiological parameter comparisons showed significant negative correlations between MMSE scores and [11C](R)PK11195 BPs in the limbic, precuneus and prefrontal regions. Direct comparisons showed significant negative correlation between [11C](R)PK11195 BPs and [11C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05 corrected) that manifest the most severe reduction in [18F]FDG uptake. Conclusions: We found all the uptake of [11C](R)PK11195, [11C]PIB and [18F]FDG similar to the literature in which each tracer was investigated separately in AD, indicating our one-day protocol measurement was advantageous to depicting pathophysiological events occurring simultaneously in vivo. The significant negative correlation between microglial activity and A accumulation in the PCC might suggest that activated microglia become less aggravated ever after marked neuronal dysfunction together with substantial A deposits develops in AD. doi:10.1016/j.neures.2010.07.1348
P2-n08 Cognitive decline in diabetes Shozo Kito 1 , Akiko Shingo 2 1
Kohshin-kai Chigasaki Central Hospital, Kanagawa Japan 2 Okinaka Memorial Institute for Medical Research, Tokyo Japan
In diabetic subjects without dementia, cognitive abilities such as memory, attention and executive/frontal lobe function are often impaired. Previously, we analyzed hippocampal and extrahippocampal morphology of out-patients of type 2 diabetes mellitus with independent ADL aged 50–85 years using VSRAD. Out of 87 patients, 59% showed atrophy of the parahippocampal gyrus (PHG) with more than 1.0 of the mean Z-score. This presentation consists of clinical and experimental studies. Clinically, repeated examinations of PHG atrophic level using VSRAD were performed on 33 patients of which 23 patients showed atrophy of PHG. Out of 23 patient, atrophy of PHG advanced in 10 patients, while retreated in 8 patients. Experimentally the following 2 kinds of rats were prepared. (1) rats in which 80 mg/kg streptozotocin (STZ) was intraperitoneally injected (STZ-rats). (2) rats in which 80 mg/kg STZ was injected intraventricularly (STZ-icv-rats, brain diabetes rats). On these 2 kinds of diabetic rats, place navigation tasks were imposed with use of Morris Water Maze measuring the total swimming distance, total swimming time, time needed to reach the platform and swimming distance due to search errors. Both of rats showed elongations in all of these parameters compared to control rats. Results were compared between 2 kinds of diabetic rats. doi:10.1016/j.neures.2010.07.1349
P2-n09 The role of ATBF1 in APP processing and  generation
Cha Gyun Jung 1 , Kyong Ok Uhm 1 , Yutaka Miura 2 , Hiroyasu Akatsu 3 , Makoto Michikawa 1 1 Department of Alzheimer’s Disease, Research Institute, National Center for Geriatrics and Gerontology (NCGG) 2 Department Mol. Neurobiol., Med., Nagoya City University, Nagoya, Japan 3 Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan
The amyloid protein, the major protein component of brain senile plaques in Alzheimer disease (AD), derived from the proteolytic cleavage of an amyloid precursor protein (APP) by - and ␥-secretase. However, the mechanisms mediating APP processing is poorly understood. ATBF1 (AT-motif binding factor 1), a homeotic transcription factor, is highly expressed in the nucleus of postmitotic neurons and its subcellular localization is linked to cell differentiation and induction of cell cycle arrest. Recently, we found that ATBF1 is highly expressed in the cytosol of neurons of AD brain compared with age-matched control. The aim of this study is to investigate whether ATBF1 affects to A production and APP processing. We found that ATBF1 enhanced A production in HEK293T and SH-SY5Y cells by transiently cotransfection with APP695 and ATBF1. And, the middle domain of ATBF1 interacted to C-terminal of APP assessed by coimmunoprecipitation experiment. In these cells, transfected ATBF1 was localized in nucleus by ATBF1 single transfection, whereas transfected ATBF1 was localized in the cytosol by cotransfection of ATBF1 with APP. In addition, APP expression and A production were attenuated by small interfering RNA-mediated knockdown of ATBF1 in the cultured rat primary cortical neurons. Furthermore, ATBF1 colocalized with APP in the cytosol of neurons of AD brain and APP transgenic mice, Tg2576. Our data suggest that cytosolic ATBF1 expression may stabilize APP, resulting in enhanced A production, and contribute to play an important role in the pathogenesis of AD brain. doi:10.1016/j.neures.2010.07.1350
P2-n10 The hippocampus in diabetes Akiko Shingo 1 , Shozo Kito 2 1
Okinaka Memorial Institute for Medical Research, Tokyo Japan 2 Kohshinkai Chigasaki Central Hospital, Kanagawa Japan
In diabetic subjects without dementia, cognitive abilities such as memory, attention and executive/frontal lobe function are often impaired. Previously, we analyzed hippocampal and extrahippocampal morphology of out-patients of type 2 diabetes mellitus with independent ADL aged 50–85 years using VSRAD. Out of 87 patients, 59% showed atrophy of the parahippocampal gyrus (PHG) with more than 1.0 of the mean Z-score. This presentation consists of clinical and experimental studies. Clinically, repeated examinations of PHG atrophic level using VSRAD was performed on 33 patients of which 23 patients showed atrophy of PHG. Out of 23 patient, atrophy of PHG advanced in 10 patients, while retreated in 8 patients. Experimentally the following 2 kinds of rats were prepared. (1) rats in which 80 mg/kg streptozotocin (STZ) was intraperitoneally injected (STZ-rats). (2) rats in which 80 mg/kg STZ was injected intraventricularly (STZ-icv-rats, brain diabetes rats). On these rats, quantitative immunohistochemistry of IGF-1, IDE (insulin degrading enzyme), SHIP2, A protein and p-CREB was performed using hippocampal tissue. As results, it was revealed that immunoreactivities of IGF-1 and IDE were decreased in both kinds of diabetic rats compared to control rats, while immunoreactivities of A protein were increased. Results were compared between 2 kinds of diabetic rats. doi:10.1016/j.neures.2010.07.1351
P2-n11 Peoteomic analysis of APP introcellular domain (AICD) accumulation in cultlured cells Fuyuki Kametani , Seiichi Haga Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research Accumulation and deposition of fibrillar amyloid beta (A) is considered the primary cause of Alzheimer’s disease (A hypothesis). However, failures of therapeutic trials based upon a modulation of A secretion or A polymers dissociation have raised some doubt about A hypothesis. A is derived from Alzheimer amyloid precursor protein (APP) by sequential proteolytic cleavage involving - and ␥-secretase. This process also yields a small intracellular fragment, the APP intracellular domain (AICD). Recent findings suggest that AICD is just a byproduct of A release, but may have some toxic effects of its
Abstracts / Neuroscience Research 68S (2010) e223–e334
P2-n07 Alterations in microglial activation and amyloid deposits in Alzheimer’s disease Yasuomi Ouchi 1 , Masamichi Yokokura 2 , Shunsuke Yagi 1 , Mitsuru Kikuchi 3 , Etsuji Yoshikawa 4 , Masami Futatsubashi 4 , Yumi Oboshi 1 , Masanobu Sakamoto 5 , Takatoshi Ueki 6 1
Molecular Imaging Frontier Res Ctr, Hamamatsu University Med Psychiatry, Hamamatsu University Med, Hamamatsu, Japan 3 Psychiatry, Kanazawa University, Kanazawa, Japan 4 Hamamatsu Photonics KK, Hamamatsu, Japan 5 Hamamatsu Medical Center, Hamamatsu, Japan 6 Anatomy, Hamamatsu University Med, Hamamatsu, Japan
2
It is well known that amyloid  protein (A) is a major pathological substance in Alzheimer’s disease (AD). A large amount of A deposits along with activated microglia is considered detrimental to neurons in the AD brain. However, it remains unclear whether these two events are pathogenic conspirators or occurring in parallel to produce cognitive decline in AD patients. The purpose of this study was to clarify the in vivo relation between A accumulation and neuroinflammation along with cognitive decline in the living AD brain. Methods: Eleven patients with AD underwent a series of positron emission tomography (PET) measurements with [11C](R)PK11195, [11C]PIB and [18F]FDG and a battery of cognitive tests within the same day. Binding potentials (BPs) for [11C](R)PK11195 and [11C]PIB and regional uptake of [18F]FDG were calculated semi-quantitatively. Results: Significant changes in BPs of [11C](R)PK11195 and [11C]PIB were found in the well-known parietotemporal regions of AD patients. The clinicalbiological parameter comparisons showed significant negative correlations between MMSE scores and [11C](R)PK11195 BPs in the limbic, precuneus and prefrontal regions. Direct comparisons showed significant negative correlation between [11C](R)PK11195 BPs and [11C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05 corrected) that manifest the most severe reduction in [18F]FDG uptake. Conclusions: We found all the uptake of [11C](R)PK11195, [11C]PIB and [18F]FDG similar to the literature in which each tracer was investigated separately in AD, indicating our one-day protocol measurement was advantageous to depicting pathophysiological events occurring simultaneously in vivo. The significant negative correlation between microglial activity and A accumulation in the PCC might suggest that activated microglia become less aggravated ever after marked neuronal dysfunction together with substantial A deposits develops in AD. doi:10.1016/j.neures.2010.07.1348
P2-n08 Cognitive decline in diabetes Shozo Kito 1 , Akiko Shingo 2 1
Kohshin-kai Chigasaki Central Hospital, Kanagawa Japan 2 Okinaka Memorial Institute for Medical Research, Tokyo Japan
In diabetic subjects without dementia, cognitive abilities such as memory, attention and executive/frontal lobe function are often impaired. Previously, we analyzed hippocampal and extrahippocampal morphology of out-patients of type 2 diabetes mellitus with independent ADL aged 50–85 years using VSRAD. Out of 87 patients, 59% showed atrophy of the parahippocampal gyrus (PHG) with more than 1.0 of the mean Z-score. This presentation consists of clinical and experimental studies. Clinically, repeated examinations of PHG atrophic level using VSRAD were performed on 33 patients of which 23 patients showed atrophy of PHG. Out of 23 patient, atrophy of PHG advanced in 10 patients, while retreated in 8 patients. Experimentally the following 2 kinds of rats were prepared. (1) rats in which 80 mg/kg streptozotocin (STZ) was intraperitoneally injected (STZ-rats). (2) rats in which 80 mg/kg STZ was injected intraventricularly (STZ-icv-rats, brain diabetes rats). On these 2 kinds of diabetic rats, place navigation tasks were imposed with use of Morris Water Maze measuring the total swimming distance, total swimming time, time needed to reach the platform and swimming distance due to search errors. Both of rats showed elongations in all of these parameters compared to control rats. Results were compared between 2 kinds of diabetic rats. doi:10.1016/j.neures.2010.07.1349
P2-n09 The role of ATBF1 in APP processing and  generation
Cha Gyun Jung 1 , Kyong Ok Uhm 1 , Yutaka Miura 2 , Hiroyasu Akatsu 3 , Makoto Michikawa 1 1 Department of Alzheimer’s Disease, Research Institute, National Center for Geriatrics and Gerontology (NCGG) 2 Department Mol. Neurobiol., Med., Nagoya City University, Nagoya, Japan 3 Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan
The amyloid protein, the major protein component of brain senile plaques in Alzheimer disease (AD), derived from the proteolytic cleavage of an amyloid precursor protein (APP) by - and ␥-secretase. However, the mechanisms mediating APP processing is poorly understood. ATBF1 (AT-motif binding factor 1), a homeotic transcription factor, is highly expressed in the nucleus of postmitotic neurons and its subcellular localization is linked to cell differentiation and induction of cell cycle arrest. Recently, we found that ATBF1 is highly expressed in the cytosol of neurons of AD brain compared with age-matched control. The aim of this study is to investigate whether ATBF1 affects to A production and APP processing. We found that ATBF1 enhanced A production in HEK293T and SH-SY5Y cells by transiently cotransfection with APP695 and ATBF1. And, the middle domain of ATBF1 interacted to C-terminal of APP assessed by coimmunoprecipitation experiment. In these cells, transfected ATBF1 was localized in nucleus by ATBF1 single transfection, whereas transfected ATBF1 was localized in the cytosol by cotransfection of ATBF1 with APP. In addition, APP expression and A production were attenuated by small interfering RNA-mediated knockdown of ATBF1 in the cultured rat primary cortical neurons. Furthermore, ATBF1 colocalized with APP in the cytosol of neurons of AD brain and APP transgenic mice, Tg2576. Our data suggest that cytosolic ATBF1 expression may stabilize APP, resulting in enhanced A production, and contribute to play an important role in the pathogenesis of AD brain. doi:10.1016/j.neures.2010.07.1350
P2-n10 The hippocampus in diabetes Akiko Shingo 1 , Shozo Kito 2 1
Okinaka Memorial Institute for Medical Research, Tokyo Japan 2 Kohshinkai Chigasaki Central Hospital, Kanagawa Japan
In diabetic subjects without dementia, cognitive abilities such as memory, attention and executive/frontal lobe function are often impaired. Previously, we analyzed hippocampal and extrahippocampal morphology of out-patients of type 2 diabetes mellitus with independent ADL aged 50–85 years using VSRAD. Out of 87 patients, 59% showed atrophy of the parahippocampal gyrus (PHG) with more than 1.0 of the mean Z-score. This presentation consists of clinical and experimental studies. Clinically, repeated examinations of PHG atrophic level using VSRAD was performed on 33 patients of which 23 patients showed atrophy of PHG. Out of 23 patient, atrophy of PHG advanced in 10 patients, while retreated in 8 patients. Experimentally the following 2 kinds of rats were prepared. (1) rats in which 80 mg/kg streptozotocin (STZ) was intraperitoneally injected (STZ-rats). (2) rats in which 80 mg/kg STZ was injected intraventricularly (STZ-icv-rats, brain diabetes rats). On these rats, quantitative immunohistochemistry of IGF-1, IDE (insulin degrading enzyme), SHIP2, A protein and p-CREB was performed using hippocampal tissue. As results, it was revealed that immunoreactivities of IGF-1 and IDE were decreased in both kinds of diabetic rats compared to control rats, while immunoreactivities of A protein were increased. Results were compared between 2 kinds of diabetic rats. doi:10.1016/j.neures.2010.07.1351
P2-n11 Peoteomic analysis of APP introcellular domain (AICD) accumulation in cultlured cells Fuyuki Kametani , Seiichi Haga Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research Accumulation and deposition of fibrillar amyloid beta (A) is considered the primary cause of Alzheimer’s disease (A hypothesis). However, failures of therapeutic trials based upon a modulation of A secretion or A polymers dissociation have raised some doubt about A hypothesis. A is derived from Alzheimer amyloid precursor protein (APP) by sequential proteolytic cleavage involving - and ␥-secretase. This process also yields a small intracellular fragment, the APP intracellular domain (AICD). Recent findings suggest that AICD is just a byproduct of A release, but may have some toxic effects of its