一般口演（Oral）

Oral Aging & Neurodegenerative Diseases 一般口演老化・神経変性疾患

7月27日（土）17:30～17:45　第9会場（朱鷺メッセ　3F　306+307） 3O-09e2-1 DNA damage with concomitant high oxidative stress and poor antioxidant enzyme activity underlie obesity and accelerated aging in WNIN/Ob obese rats. Jitendra Kumar Sinha（Sinha Jitendra Kumar）^1,2，Shampa Ghosh（Ghosh Shampa）²，Manchala Raghunath（Raghunath Manchala）² ¹Amity University ²National Institute of Nutrition, ICMR, Tarnaka, Hyderabad 500007 India Disequilibrium between the production of reactive oxygen and ability of an organism to readily detoxify the reactive intermediates or easily repair the resulting damage is termed as oxidative stress (OS). OS is believed to be involved in development of various pathologies like Alzheimer's disease, cancer, accelerated aging and many others. On the other hand, OS itself arises from medical conditions like obesity. Wistar of National Institute of Nutrition obese (WNIN/Ob) rat is a novel strain developed at National Institute of Nutrition, Hyderabad, India. These rats have significantly reduced average lifespan of 15-18 months in contrast to 36 months in normal WNIN rats. These are the heaviest inbred rats recorded in literature, weighing up to 1.47 Kg. These rats exhibit typical Mendelian ratio of 1:2:1 in distribution of phenotypes (+/+ lean, +/&mn carrier, and &mn/&mn obese) with autosomal incomplete dominance as the mode of inheritance. These rats are euglycemic and show characteristic features of obesity with insulin resistance like hyperinsulinemia, hyperleptinemia, hypertriglyceridemia and hypercholesterolemia along with hyperphagia, polydipsia, polyuria and proteinuria in addition to other secondary complications associated with metabolic syndrome. The coding sequence of leptin and its receptor remains unchanged in these rats but they exhibit leptin resistance. Our studies clearly show the progression of OS and accumulation of DNA damage in brain at an early age causing accelerated aging in these rat models. Imbalance in the levels of trophic factors IGF1 and BDNF, both in plasma and brain, implies altered signaling which in turn leads to hyperphagic behavior and stress. The increased C-reactive protein levels and astroglial infiltration further give clues regarding increased cellular stress and damage in important brain areas like hypothalamus, hippocampus and cerebral cortex. Here the link between obesity and brain aging has been proposed with future directions of research. Ethical Statement: This study was performed in accordance with the protocols duly approved by the institutional animal ethical committee. Source of funding: Indian Council of Medical Research, New Delhi.		7月27日（土）17:45～18:00　第9会場（朱鷺メッセ　3F　306+307） 3O-09e2-2 老齢雌マウスの脳における8‐オキソグアニンの蓄積は歯状回および大カレハ島における神経新生を低下させ、性的二形の原因となる Yusaku Nakabeppu（中別府雄作）¹，Naoki Haruyama（春山直樹）^1,2，Kunihiko Sakumi（作見邦彦）¹，Atsuhisa Katogi（加藤木敦央）¹，Daisuke Tsuchimoto（土本大介）¹，Gabriele De Luca（De Luca Gabriele）³，Margherita Bignami（Bignami Margherita）⁴ ¹九州大学生体防御医学研究所 ²九州大学大学院医学研究院病態機能内科学 ³Department of Oncology and Molecular Medicine, Istituto Superiore di Sanitá, Rome, Italy ⁴Department of Environment and Health, Istituto Superiore di Sanitá, Rome, Italy Neurons need to survive and function throughout the life of the individual. However, postmitotic neurons are known to be lost owing to dysfunction associated with aging, particularly via oxidative stress. Consequently, several defense mechanisms function to retain neural networks, including the supply of newborn neurons from neural progenitors in the adult brain. Despite the many defense mechanisms evolved by eukaryotic cells, various oxidized lipids, proteins, carbohydrates and nucleic acids have been found to accumulate in the brains of animals including humans during aging, and under pathological conditions. Among all nucleobases, guanine is the most susceptible to oxidation, and is modified to 8-oxo-7,8-dihydro-guanine (8-oxoG), which is one of the major oxidized bases in the nucleotide pool or DNA, and is known to be highly accumulated in patient's brains with aging-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoG DNA glycosylase minimize 8-oxoG accumulation in genomic DNA. In the present study, we investigated age-related alterations in behavior, 8-oxoG levels, and neurogenesis in the brains of Mth1/Ogg1-double knockout (TO-DKO), Ogg1-knockout, and human MTH1-transgenic (hMTH1-Tg) mice. Spontaneous locomotor activity in the home cage was significantly decreased in wild-type mice with age, and females consistently exhibited higher locomotor activity than males. This decrease was significantly suppressed in female but not male TO-DKO mice and markedly enhanced in female hMTH1-Tg mice. Long-term memory retrieval was impaired in middle-aged female TO-DKO mice. 8-OxoG accumulation significantly increased in nuclear DNA, particularly in the dentate gyrus (DG), subventricular zone (SVZ) and major island of Calleja (ICjM) in middle-aged female TO-DKO mice. In middle-aged female TO-DKO mice, neurogenesis was severely impaired in SVZ and DG, accompanied by ICjM and DG atrophy. Conversely, expression of hMTH1 efficiently suppressed 8-oxoG accumulation in both SVZ and DG with hypertrophy of ICjM. These findings indicate that increased accumulation of 8-oxoG in nuclear DNA of neural progenitors in females is caused by 8-oxo-dGTP incorporation into the nuclear genome during proliferation, causing depletion of neural progenitors, altered behavior, and cognitive function changes with age, as sexually dimorphic phenotypes.

7月27日（土）18:00～18:15　第9会場（朱鷺メッセ　3F　306+307） 3O-09e2-3 Deficiency of Progranulin (PGRN) results in accelerated prion diseases Caihong Zhu（Zhu Caihong），Petra Schwarz（Schwarz Petra），Adriano Aguzzi（Aguzzi Adriano） Institute of Neuropathology Introduction: Progranulin (PGRN) is a secreted glycoprotein expressed mainly by microglia and neurons in in the central nervous system. Mutations in PGRN encoding gene GRN that result in haploinsufficiency lead to frontotemporal lobar degeneration and Alzheimer's diseases. However, the underlying molecular mechanisms remain largely unknown. To determine whether PGRN is involved in a broad spectrum of neurodegenerative conditions including prion disease, we aimed to delineate the role of PGRN in prion pathogenesis. Methods: We intracerebrally infected GRN^-/- mice and their GRN^+/- and wild type littermates with RML6 prions. Survival curves determined by the time lapse between the prion inoculation and end stage of disease were compared between the three genotypes. Vacuolation, lesion pattern, PrP^Sc deposition, astrogliosis and microglial activation in RML6-infected GRN^-/- mice and their GRN^+/- and wild type littermates were characterized by histology and biochemistry. Results: We found that GRN^-/- mice showed accelerated prion progression in comparison to GRN^+/- and wild type littermates, suggesting that complete GRN deficiency, but not haploinsufficiency, is a determinant of prion pathogenesis. Histology revealed that GRN^-/- microglia were aberrantly activated, resulting in amoeboid morphology and altered cytokine profiles. Biochemical analysis demonstrated that at 120 days post prion inoculation (dpi), GRN^-/- microglia were more activated and competent to clear prions, resulted in decreased prion deposition. Whereas at 150dpi, over-activation of GRN^-/- microglia led to excessive complement activation and insufficiency of prion clearance, resulting in similar level of PrP^Sc to that of GRN^+/- and wild type littermates. These results suggest that Progranulin modulates prion-induced microglial activation and protects prion diseases by suppressing excessive activation of complement cascade. Conclusions: Microglial activation by prion infection is a stepwise process. Progranulin is an important negative regulator of prion-induced microglial activation. Depletion of PGRN resulted in aberrant microglial activation and accelerated prion disease, suggesting that Progranulin could be a potential target for prion therapeutics.		7月27日（土）18:15～18:30　第9会場（朱鷺メッセ　3F　306+307） 3O-09e2-4 LRRK2欠損マウスにおける腸管神経新生異常と異常腸管運動 Tatsunori Maekawa（前川達則），Fumitaka Kawakami（川上文貴），Rei Kawashima（川島麗），Takafumi Ichikawa（市川尊文）北里大医療衛生 Background: Leucine-rich repeat kinase 2 (LRRK2) is a molecule associated with familial and sporadic Parkinson's disease. It regulates many central neuronal functions such as cell proliferation, apoptosis, autophagy, and axonal extension. Our recent findings showed that LRRK2 is expressed in enteric neurons as well as brain neurons. In this study, we analyzed a diversity of enteric neurons and gut motility of LRRK2-knockout (KO) mice using ex vivo gut preparations. Methods: Gut samples were prepared from LRRK2-KO and wild-type (WT) mice after cervical dislocation. Longitudinal muscle myenteric plexus (LMMP) obtained from both mice were used for immunofluorescence analysis. Gut motility was recorded by a video camera following equilibration in organ bath. Data was converted to spatiotemporal map via software package given by Dr. Bornstein (Melbourne University). Results: Immunofluorescence analysis of LMMP showed no differences between LRRK2-KO and WT mice regarding a proportion of major subtypes of enteric neurons. The proportion of neuron expressing both Sox2 and Hu was increased in KO mice in comparison with WT mice. Spatiotemporal map revealed that KO mice have more fragmented and partial colonic migrating motor complexes (CMMC) and the irregular interval between CMMCs even though the total number of CMMCs was comparable to that of WT mice. NOS inhibition alleviated this aberrant CMMCs of KO mice, accompanied by increasing the number of CMMCs. Conclusions: We revealed that LRRK2 is associated with disruption of glial neurogenesis and a periodic gut motility which seem to be caused by disrupted nitrergic neuronal regulation.