Oral Session

Oral Session 8 一般口演8

O8-1 Tau filaments in cellular and mouse models of tauopathy タウオパチーモデルにおける線維状タウ凝集体の構築 Sahara Naruhiko（佐原成彦）¹，松本弦²，山口芳樹³ ¹National Institutes for Quantum and Radiological Science and Technology, NIRS, Chiba ²Dept. Anatomy and Neurobiology, School of Med. Nagasaki Univ., Nagasaki ³RIKEN, Wako Neurofibrillary tangles composed of hyperphosphorylated tau protein are primarily neuropathological features of a number of neurodegenerative diseases, collectively termed tauopathy. To understand the mechanisms underlying cause of tauopathy, precise cellular and animal models are required. Recent data suggest that transient introduction of exogenous tau can accelerate the development of tauopathy in the brains of non-transgenic and transgenic mice expressing wild-type human tau. However, the transmission mechanism leading to tauopathy is not fully understood. Currently, we developed cultured-cell models of tauopathy representing a human tauopathy. These cell line containing propagative tau filaments were generated by introducing purified tau fibrils. These cell lines expressed full-length human tau and GFP-fused repeat domain of tau with P301L mutation. Live-cell imaging analysis revealed that filamentous tau inclusions are transmitted to daughter cells, resulting in yeast-prion like propagation. By a standard method of tau preparation, both full-length tau and repeat domain fragment were recovered in the sarkosyl insoluble fraction. Hyperphosphorylation of full-length tau was confirmed by immunoreactivity of phospho-Tau antibodies and mobility sifts in SDS-PAGE. These properties were similar to the biochemical features of P301L mutated human tau in a mouse model of tauopathy. To further characterize filamentous structures of tau aggregates, super-resolution microscopic and electron microscopic analyses are ongoing. Taken together, present tauopathy models will provide an advantage for dissecting the mechanisms of tau aggregation and be a powerful tool for a drug screening to prevent tauopathy.		O8-2 HDAC3 inhibition ameliorates memory function via regulating microglial phenotype in Alzheimer's disease model mice アルツハイマー病モデルマウスにおいてHDAC3阻害はマイクログリアの表現型制御を介して記憶を改善させる Kuboyama Tomoharu（久保山友晴），東田千尋 Div of Neuromedical Science, Instit of Natural Med, Univ of Toyama Many studies suggest that Alzheimer’s disease is an inflammatory disease. Brain inflammation is related to activation of microglia, especially M1 subtype. On the other hand, another type of microglia in the brain, M2 microglia plays a role of anti-inflammatory and neurotrophic effects. We previously clarified that HDAC3 inhibition induced predominance of M2 microglia and recovered locomotor function in spinal cord injured mice. Therefore, this study is aimed to clarify HDAC3 inhibition increases predominance of M2 microglia and restored memory function in Alzheimer’s disease model mice. An HDAC3 inhibitor, RGFP966 was intraperitoneally administered to 5XFAD mice, a transgenic model of Alzheimer’s disease. RGFP966 improved novel object recognition memory in 5XFAD mice. When microglia in the brain of 5XFAD mice were eliminated by intracerebroventricular administration of clophosome, the effect of RGFP966 was diminished. In cultured microglia, amyloid β treatment skewed toward M1 microglia, whereas RGFP966 treatment skewed toward M2 microglia when treated 24 h after amyloid β addition. These results indicate that HDAC3 inhibition increased predominance of M2 microglia and ameliorated memory in 5XFAD mice. We propose RGFP966 is a novel anti-Alzheimer’s disease drug candidate which regulates microglial phenotype.

O8-3 Increased cerebrospinal fluid fibrinogen and brain-blood barrier disruption in a subpopulation of psychiatric disorders 精神疾患の一部症例における脳脊髄液中fibrinogenの亢進と血液脳関門障害 Hattori Kotaro（服部功太郎）¹，宮川友子²，篠山大明¹，秀瀬真輔¹，野田隆正³，吉田寿美子^2,3，功刀浩¹ ¹Dept. Mental Disorder Res., Nat. Inst. Neurosci., NCNP ²Medical Genome Center, NCNP ³NCNP Hospital Psychiatric disorders including major depressive disorder (MDD) presumably include heterogeneous subgroups with differing pathologies. We previously reported that a subpopulation of MDD patients had high CSF fibrinogen levels and white matter tract abnormalities. In the present study, we expanded that study by measuring CSF fibrinogen levels in a total of 356 samples from 96 MDD, 91 schizophrenia, 59 bipolar disorder (BD) patients and 110 controls. The frequency of high fibrinogen subjects (>99 percentile of controls) was increased across these disorders compared to the controls (all p<0.01, Fisher's exact test). Similar results were observed in 97 psychiatric samples from the Max Planck Institute of Psychiatry. We also analyzed CSF fibrinogen levels in 17 patients who received electroconvulsive therapy (ECT). The fibrinogen levels significantly decreased after ECT (p<0.05, paired t-test). We then measured the CSF/plasma albumin ratio (Q-Alb), a marker for blood-brain barrier (BBB) integrity, in 266 cases. The fibrinogen levels significantly correlated with Q-Alb (Spearman's rho=0.77). Because fibrinogen levels are ~1000 times higher in plasma compared to CSF, the increased CSF fibrinogen levels among psychiatric patients might be the result from BBB disruption. Our results suggest that a common pathophysiology may be present in a subpopulation of patients across the major psychiatric disorders that is represented by increased CSF fibrinogen levels, which would lead to the brain dysfunction.