一般口演（Oral）

Oral Alzheimer's disease-1 一般口演アルツハイマー病-1

7月27日（土）14:20～14:35　第8会場（朱鷺メッセ　3F　303+304） 3O-08a1-1 アルツハイマー病モデルトランスジェニックマウスにおいてHDAC3阻害はマイクログリアのM2化を介して記憶を改善させる Tomoharu Kuboyama（久保山友晴），Chihiro Tohda（東田千尋）富山大和漢研神経機能学 Amyloid β (Aβ) skews microglia to M1 phenotype and induces inflammation and neurodegeneration. On the other hand, another type of microglia, M2, shows anti-inflammatory and neurotrophic effects. We previously clarified that HDAC3 inhibition induced predominance of M2 microglia and axonal growth, and recovered locomotor function in spinal cord injured mice. Therefore, this study aimed to clarify that HDAC3 inhibition skewed to 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, RGFP966 treatment skewed to M2 microglia when treated 24 h after Aβ addition. Conditioned medium was collected from RGFP966-treated microglia, which recovered Aβ-induced collapse of axonal growth cones. These results suggest that HDAC3 inhibition increased predominance of M2 microglia, recovered axonal degeneration, and ameliorated memory deficit in 5XFAD mice.		7月27日（土）14:35～14:50　第8会場（朱鷺メッセ　3F　303+304） 3O-08a1-2 The Neuroprotective Effects of Digoxin to Alzheimer’s dementia model: An Experimental Rat Model Mumin Alper Erdogan（Erdogan Mumin Alper）¹，Gurkan Yigitturk（Yigitturk Gurkan）²，Oytun Erbas（Erbas Oytun）³ ¹Izmir Katip Celebi University, Faculty of Medicine, Department of Physiology ²Mugla Sitki Kocman University, Faculty of Medicine, Department of Histology and Embryology ³Istanbul Bilim University, Faculty of Medicine, Department of Physiology Aims: Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, which causes progressive development of cognitive deficits with severe learning and memory loss, behavioral changes and eventually to morbidity and death. A complex mechanism for pathogenesis of AD has been recently proposed that involves an increase in inflammation. TNF-α is the major cytokine synthesized by activated microglia and neurons and initiating the inflammatory cascade. Examinations of postmortem AD brains has revealed that increased TNF-α co-localizes with Aβ plaques. IL-17 and TNF-α are also known to interplay and drive common molecular pathways. Although IL-17 can induce pro-inflammatory cytokines by itself, its effects are vastly increased when cooperating with TNF-α. Because Digoxin has some anti-inflammatory features due to inhibitory effects on IL-17/TNF-α in previous animal studies, we investigated the effects of Digoxin in an intracerebroventricular (ICV)-streptozotocin (STZ) animal model of sporadic-AD. Methods: A total of 18 Sprague-Dawley adult rats were divided into 3 groups of control (n=6), ICV-STZ+saline (n=6) and ICV-STZ+Digoxin (n=6). Twelve rats with AD, induced by STZ injection (3 mg/kg) into both lateral ventricles using a stereotaxic frame, were divided into 2 groups 5 days after the STZ injection: one treated with Digoxin (0.1 mg/kg/day, i.p.) and the other with 0.9% NaCl (1 ml/kg/day, i.p.) for 3 weeks. No surgery/treatment was given to the controls. After treatment, a passive avoidance learning (PAL) test was used followed by removal of the brain tissue in all animals. Brain TNF-α and ChAT levels were determined, and neurons in the hippocampal CA1 and CA3 regions were counted by Cresyl violet staining. Results: ICV-STZ was found to significantly shorten the latency time on the PAL, increase brain TNF-α level, decrease brain ChAT activity and neuron counts in the hippocampus. On the other hand, Digoxin significantly attenuated all these detrimental effects induced by STZ. Conclusions: Digoxin significantly prevented the ICV-STZ-induced memory deficit by attenuating the hippocampal neuronal loss, neuroinflammation and cholinergic deficit in rats. These findings suggest that Digoxin may be beneficial for treating AD. Keywords: Alzheimer's disease, Digoxin, streptozotocin, neuroprotection, hippocampus

7月27日（土）14:50～15:05　第8会場（朱鷺メッセ　3F　303+304） 3O-08a1-3 Cdk5はMARK4の活性を増加させてSer262のリン酸化を介したタウの蓄積と毒性を増強する Taro Saito（斎藤太郎）¹，Toshiya Oba（大場俊弥）¹，Sawako Shimizu（清水彩和子）¹，Akiko Asada（浅田明子）¹，Koichi M Iijima（飯島浩一）^2,3，Kanae Ando（安藤香奈絵）¹ ¹首都大学東京理学研究科生命科学専攻 ²国立長寿医療研究センター ³名古屋市立大学薬学研究科 Hyperphosphorylation of the microtubule-associated protein tau is associated with many neurodegenerative diseases, including Alzheimer's disease. Microtubule affinity-regulating kinases (MARK1-4) and cyclin-dependent kinase 5 (Cdk5) are tau kinases under physiological and pathological conditions. However, their functional relationship remains elusive. Here, we report a novel mechanism by which Cdk5 activates MARK4 and augments tau phosphorylation, accumulation, and toxicity. MARK4 is highly phosphorylated at multiple sites in the brain and in cultured neurons, and inhibition of Cdk5 activity reduces phosphorylation levels of MARK4. MARK4 is known to be activated by phosphorylation at its activation loop by LKB1. In contrast, Cdk5 increased phosphorylation of MARK4 in the spacer domain, but not in the activation loop, and e n hanced its kinase activity, suggesting a novel mechanism by which Cdk5 regulates MARK4 activity. We also demonstrated that co-expression of Cdk5 and MARK4 in mammalian cultured cells significantly increased the levels of tau phosphorylation at both Cdk5 target sites (SP/TP sites) and MARK target sites (Ser262), as well as the levels of total tau. Furthermore, using a Drosophila model of tau toxicity, we demonstrated that Cdk5 promoted tau accumulation and tau-induced neurodegeneration via increasing tau phosphorylation levels at Ser262 by a fly ortholog of MARK, Par-1. This study suggests a novel mechanism by which Cdk5 and MARK4 synergistically increase tau phosphorylation and accumulation, consequently promoting neurodegeneration in disease pathogenesis.		7月27日（土）15:05～15:20　第8会場（朱鷺メッセ　3F　303+304） 3O-08a1-4 認知症における凝集前神経変性の共通病態としてのMARCKSリン酸化 Kyota Fujita（藤田慶大），Hidenori Homma（本間秀典），Kanoh Kondo（近藤和），Kazuhiko Tagawa（田川一彦），Hitoshi Okazawa（岡澤均）東京医科歯科大難治疾患研究所神経病理 Protein aggregation is a widely accepted hallmark of neurodegenerative disorders. However, the details of chronological and stochastic changes remain largely unknown, triggering debates about the identities of the true toxic species, as well as whether aggregated or soluble proteins are toxic. Clinical trials of AD therapeutics targeting extracellular Aβ plaques in the brain reported discrepancies between improvements in Aβ -PET and amelioration of clinical symptoms. So, elucidation of early-stage pathologies is now an urgent issue for understanding pathogenesis and developing therapeutics of AD as well as other neurodegenerative diseases including PD/DLB. Using comprehensive phosphoproteomic analysis of brain samples from mouse AD models and human AD patients, we revealed that changes in the phosphorylation of some proteins are initiated before Aβ plaques are histologically detectable. In one such protein, MARCKS, phosphorylation at Ser46 can be detected in degenerated neuritis of mice at the age of 1 month, prior to cognitive symptoms and Aβ plaques. Simillar phosphorylation of MARCKS at Ser46 has been detected in BAC-Tg mice overexpressing human normal α-synuclein (α-Syn) in the glucocerebroside (GBA)-heterozygous-knockout (KO) background, as well as in human DLB patients. The histologic features of phosphorylation of MARCKS on serine 46 (pSer46-MARCKS) and chronological progression in the brain were similar in AD and PD/DLB. Intriguingly, this marker of neurodegeneration became positive before formation of histologically detectable α-Syn aggregates. These results cast light on the relationship between neuronal degeneration and protein aggregation, and reveal that the initiation of neurite degeneration precedes formation of protein aggregates.