Oral Session

Oral Session 5 一般口演5

O5-1 SUMO1 impact on Alzheimer disease pathology in an amyloiddepositingmouse model SUMO1はアルツハイマー病モデルマウスにおけるアミロイドβタンパク質蓄積に影響する Matsuzaki Shinsuke（松崎伸介）^1,2，Knock Erin³，高村明孝^2,3，佐藤嘉名与³，天野元揮²，小林大地¹，雑賀史浩¹，木口倫一¹，片山泰一²，Ottavio Arancio⁴，Fraser Paul³，岸岡史郎¹ ¹Department of Pharmacology, Wakayama Medical University, Wakayama, Japan ²Molecular Brain Science, United Graduate School of Child Development, Osaka University, Suita, Japan ³Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Canada ⁴Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, NY, US Small ubiquitin-related modifiers (SUMOs) conjugated or bound to target proteins can affect protein trafficking, processing and solubility. SUMOylation has been suggested to play a role in the amyloid plaque and neurofibrillary tangle pathology of Alzheimer disease (AD) and related neurodegenerative diseases. The current study examines the impact of SUMO1 on processing of the amyloid precursor protein (APP) leading to the production and deposition of the amyloid-β (Aβ) peptide. An in vivo model of these pathways was developed by the generation of double transgenic mice over-expressing human SUMO1 and a mutant APP. The SUMO1-APP transgenics displayed normal APP processing but, at later ages, exhibited increased insoluble Aβ and plaque density accompanied by increased dendritic spine loss, more pronounced synaptic and cognitive deficits. These findings suggest a potential impairment in Aβ clearance as opposed to increased amyloid production. Examination of microglia indicated a reduction in the SUMO1-APP transgenics which is a possible mechanism for the SUMO1-mediated increase in amyloid load. These findings suggest an indirectactivity of SUMO1 possibly in the removal of Aβ plaques rather than a direct impact on amyloid generation.		O5-2 Investigation of the relationship between brain inflammation and depressive symptoms using a lipopolysaccharide-induced depressive-like model mouse リポポリサッカリド誘発うつ病様モデルマウスを用いた脳の炎症と抑うつ症状との関係の検討 Koga Minori（古賀農人）^1,2，中川伸^2,3，牧原圭祐³，岡松彦³，久住一郎³ ¹Department of Psychiatry, National Defense Medical College, Saitama, Japan ²Division of Neuropsychiatry, Department of Neuroscience, Yamaguchi University Graduate School of Medicine ³Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan Recent studies indicate that abnormal inflammation is involved in the pathogenesis of depression. In the present study, chronological gene expression changes involved in inflammatory depressive symptoms were investigated using depression-like behavior model mice by lipopolysaccharide (LPS) administration. ICR mice (10 weeks old, male) were administered with 0.83mg/kg LPS 1, 3 and 7 days before the behavioral test (LPS groups, n=16 for each). The control group (n=16) was given the same amount of normal saline. A forced swim test was conducted to evaluate depressiveness after administration. Total RNA was extracted from the prefrontal cortex, hippocampus, and striatum, and quantitive PCR was performed for comparative analysis of genes involved in inflammation between the LPS and the control groups. The immobility ratios of mice 1, 3 and 7 days after LPS administration were significantly higher than the control group. The gene expression of IL-1β in the prefrontal cortex was 7.5±1.1 and 2.6±1.1 times higher in the mice 1 and 3 days after LPS administration compared to the control group (p<0.0001, Steel-Dwass test). However, no significant change of IL-1β gene expression in the prefrontal cortex was shown in the LPS group on the seventh day from the administration compared to the control group. In contrast, the expression level of GFAP (a marker for astrocytes) gene in the striatum was significantly higher even on the seventh day from LPS administration compared to the control mice. The findings from the analysis of chronological changes in behavior and gene expression level in the LPS-induced depressive-like behavior model mice indicated candidate genes involved in inflammatory depressive symptoms and development of depression via inflammation.

O5-3 Type 2 diabetes mellitus aggravates endocytic disturbance via elevated membrane cholesterol: mechanism underlying augmentation of age-dependent Aβ pathology 2型糖尿病は生体膜コレステロール量の上昇を介してエンドサイトーシス障害を増悪化し、Aβの蓄積を加速化する Kimura Nobuyuki（木村展之）¹，竹内真吾¹，上田直也¹，鈴木恵子¹，下澤律浩²，保富康弘² ¹Section of Cell Biol & Pathol., Dept. Alzheimer's Dis. Res., NCGG ²Tsukuba Primate Research Center, NIBIOHN Accumulating evidence shows that the endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer’s disease (AD) patients. Endocytic disturbance affects the metabolism of β-amyloid protein (Aβ), a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. We have previously shown that T2DM enhances Aβ pathology, even in nonhuman primate brains and that age-related endocytic disturbance is also aggravated in T2DM-affected monkey brains. However, it remains unclear how T2DM exacerbates endocytic disturbance to enhance Aβ pathology. Here, we demonstrate that cholesterol synthesis-related genes are upregulated and that membrane cholesterol level is elevated in T2DM-affected monkeys. Moreover, our in vitro studies reveal that the manipulation of cellular cholesterol disrupts lysosomal degradation and aggravates chloroquine-induced endocytic disturbance, resulting in increased accumulation of Aβ. These findings suggest that alteration of cholesterol metabolism may be responsible for the exacerbation of age-related endocytic disturbance in T2DM-affected brains, which in turn may increase the risk for developing AD accompanied by enhanced Aβ pathology.