Faculty Profiles - MORIHARA Ryuuta

Papers - MORIHARA Ryuuta

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A case of a heterozygous ABCC6 mutation showing recurrent ischemic strokes and intracranial hemorrhages

Emi Nomura, Yuko Kawahara, Yoshio Omote, Yoshiaki Takahashi, Namiko Matsumoto, Ken Ikegami, Mami Takemoto, Nozomi Hishikawa, Yumiko Nakano, Taijun Yunoki, Ryuta Morihara, Masahiro Uemura, Koji Abe, Toru Yamashita

Neurology and Clinical Neuroscience 10 ( 2 ) 98 - 101 2022.3

Publishing type：Research paper (scientific journal)

Mutations in the ATP-binding cassette subfamily C member 6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE). PXE is a rare genetic metabolic disease with autosomal recessive inheritance that shows ectopic mineralization in skin, eyes, and blood vessels and causes cerebrovascular disease. There are few reports of intracranial hemorrhages in patients with the ABCC6 mutation. We report the first Japanese case with a heterozygous ABCC6 mutation displaying recurrent ischemic strokes and intracranial hemorrhages. We propose that the ABCC6 mutation may be one cause of neurovascular diseases with a family history.

DOI： 10.1111/ncn3.12575

Chronic Beneficial Effect of Makeup Therapy on Cognitive Function of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software. International journal

Koh Tadokoro, Toru Yamashita, Junko Sato, Yoshio Omote, Mami Takemoto, Ryuta Morihara, Koichiro Nishiura, Tomiko Tani, Koji Abe

Journal of Alzheimer's disease : JAD 85 ( 3 ) 1189 - 1194 2022

Language：English Publishing type：Research paper (scientific journal) Publisher：IOS PRESS

BACKGROUND: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. OBJECTIVE: To evaluate the therapeutic effect of makeup therapy. METHODS: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n = 16) or skin care plus makeup therapy (makeup therapy group, n = 18) once every 2 weeks for 3 months were assessed. RESULTS: Three months of makeup therapy significantly improved the Mini-Mental State Examination (MMSE) score compared with control patients ( *p < 0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression ( *p < 0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r = 0.43, *p < 0.05). CONCLUSION: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software.

DOI： 10.3233/JAD-215385

Protective Effect of Rivaroxaban Against Amyloid Pathology and Neuroinflammation Through Inhibiting PAR-1 and PAR-2 in Alzheimer's Disease Mice. International journal

Zhihong Bian, Xia Liu, Tian Feng, Haibo Yu, Xiao Hu, Xinran Hu, Yuting Bian, Hongming Sun, Koh Tadokoro, Mami Takemoto, Taijun Yunoki, Yumiko Nakano, Yusuke Fukui, Ryuta Morihara, Koji Abe, Toru Yamashita

Journal of Alzheimer's disease : JAD 86 ( 1 ) 111 - 123 2022

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer's disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. OBJECTIVE: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. METHODS: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. RESULTS: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. CONCLUSION: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

DOI： 10.3233/JAD-215318

Scallop-Derived Plasmalogen showed Neuroprotective and inflammation Effects in a Mouse Model of Ischemic Stroke

胡欣冉, 馮田, 福井裕介, 田所功, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 山下徹

日本脳サプリメント学会(Web) 4th 2022

Three cases of GFAP astrocytopathy, one with bilateral ovarian teratoma

Yosuke Osakada, Yoshio Omote, Yuki Taira, Chika Matsuoka, Ken Ikegami, Koh Tadokoro, Emi Nomura, Yuko Kawahara, Kota Sato, Yuka Terasawa, Nozomi Hishikawa, Ryuta Morihara, Mami Takemoto, Akio Kimura, Takayoshi Shimohata, Toru Yamashita, Koji Abe

Neurology and Clinical Neuroscience 10 ( 1 ) 30 - 34 2021.11

外傷と脳循環代謝 in vitro及びin vivo血栓モデルにおける温熱照射と超音波照射の有効性と安全性の検討

森原隆太, 馮田, 小坂田陽介, 山下徹, 胡欣冉, 福井祐介, 田所功, 武本麻美, 阿部康二

脳循環代謝 33 ( 1 ) 49 - 49 2021.11

Accelerated accumulation of fibrinogen peptide chains with Aβ deposition in Alzheimer's disease (AD) mice and human AD brains. International journal

Zhihong Bian, Toru Yamashita, Xiaowen Shi, Tian Feng, Haibo Yu, Xiao Hu, Xinran Hu, Yuting Bian, Hongming Sun, Koh Tadokoro, Mami Takemoto, Yoshio Omote, Ryuta Morihara, Koji Abe

Brain research 1767 147569 - 147569 2021.9

Language：English Publishing type：Research paper (scientific journal)

Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by the abnormal accumulation of intracellular and extracellular amyloid-β (Aβ) as well as disruption of the blood brain barrier (BBB). Fibrinogen plays an essential role in regulating thrombosis, wound healing, and other biological functions. In the present study, we investigated the relationship between three polypeptide chains α, β, and γ (FGA, FGB, and FGG) and Aβ deposition in the APP23 plus chronic cerebral hypoperfusion (CCH) mice model as well as the human AD brain. FGA, FGB, and FGG accumulated when Aβ was deposited in neural cells and cerebral vessels. This deposition was significantly higher in AD plus CCH mice models relative to wild-type brains, and in human AD brains compared to control brains. The present study demonstrates that FGA, FGB, and FGG are associated with AD progress, and can thus be potential targets for the diagnosis and therapy of AD.

DOI： 10.1016/j.brainres.2021.147569

Neuroprotective effects of Scallop-derived plasmalogen in a mouse model of ischemic stroke. International journal

Tian Feng, Xinran Hu, Yusuke Fukui, Koh Tadokoro, Zhihong Bian, Ryuta Morihara, Toru Yamashita, Koji Abe

Brain research 1766 147516 - 147516 2021.9

Language：English Publishing type：Research paper (scientific journal)

Scallop-derived plasmalogen (sPlas) has both anti-oxidative and anti-inflammation activities, but its efficacy has not been investigated in ischemic stroke models where oxidative stress, inflammation, and neurovascular unit (NVU) damage accelerates pathophysiological progression. Therefore, in the present study, we aimed to assess the neuroprotective effects of sPlas in ischemic stroke by using a transient middle cerebral artery occlusion (tMCAO) mouse model. After the pretreatment of vehicle or sPlas (10 mg/kg/day) for 14 days, adult male mice were subjected to tMCAO for 60 min, then continuously treated with vehicle or sPlas during reperfusion and for an additional 5 days. The administration of sPlas significantly improved motor deficits (corner and rotarod tests, *p < 0.05 vs vehicle), enhanced serum antioxidative activity (OXY-adsorbent and d-ROMs tests, *p < 0.05 vs vehicle), reduced infarction volume (*p < 0.05 vs vehicle), decreased the expression of two oxidative stress markers, 4-HNE (*p < 0.05 vs vehicle) and 8-OHdG (*p < 0.05 vs vehicle), decreased the expression of pro-inflammatory markers Iba-1 (**p < 0.01 vs vehicle), IL-1β (**p < 0.01 vs vehicle), and TNF-α (**p < 0.01 vs vehicle), and alleviated NVU damage (collagen IV, MMP9, and GFAP/collagen IV, *p < 0.05 vs vehicle). Our present findings are the first to demonstrate the neuroprotective effects of sPlas on acute ischemic stroke mice at 5 d after tMCAO via anti-oxidative stress, anti-inflammation, and improvement of NVU damage, suggesting the potential of sPlas in preventing and treating ischemic stroke.

DOI： 10.1016/j.brainres.2021.147516

Successful treatment of anti-GAD antibody-associated autoimmune cerebellar ataxia with combined immunotherapies

Yoshio Omote, Chika Matsuoka, Ryo Sasaki, Nozomi Hishikawa, Yuko Kawahara, Emi Nomura, Namiko Matsumoto, Yuki Taira, Mami Takemoto, Ryuta Morihara, Toru Yamashita, Koji Abe

NEUROLOGY AND CLINICAL NEUROSCIENCE 2021.9

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Anti-glutamic acid decarboxylase (GAD) antibody (Ab)-associated autoimmune cerebellar ataxia (CA) is a rare neurological disorder, and a standardized therapy has not been established. Here, we report on a 58 year-old man with type 1 diabetes mellitus, who developed progressive CA with high levels of serum and cerebrospinal fluid (CSF) anti-GAD-Ab. He was initially treated with intravenous high-dose methylprednisolone and intravenous immunoglobulin (IVIg), but his CA was gradually worsened. Additional combined immunotherapies with plasma exchange, intravenous cyclophosphamide, and rituximab finally stabilized the progressive CA and suppressed the CSF anti-GAD-Ab index. Our case suggests the effectiveness of combined immunotherapies against progressive CA and the usefulness of the CSF anti-GAD-Ab index as a therapeutic indicator.

DOI： 10.1111/ncn3.12541

Early detection of cognitive decline in mild cognitive impairment and Alzheimer's disease with a novel eye tracking test. International journal

Koh Tadokoro, Toru Yamashita, Yusuke Fukui, Emi Nomura, Yasuyuki Ohta, Setsuko Ueno, Saya Nishina, Keiichiro Tsunoda, Yosuke Wakutani, Yoshiki Takao, Takahiro Miyoshi, Yasuto Higashi, Yosuke Osakada, Ryo Sasaki, Namiko Matsumoto, Yuko Kawahara, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Ryuta Morihara, Koji Abe

Journal of the neurological sciences 427 117529 - 117529 2021.8

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER

Due to an increasing number of dementia patients, the development of a rapid and sensitive method for cognitive assessment is awaited. Here, we examined the usefulness of a novel and short (3 min) eye tracking device to evaluate the cognitive function of normal control (NC, n = 52), mild cognitive impairment (MCI, n = 52), and Alzheimer's disease (AD, n = 70) subjects. Eye tracking total score declined significantly in MCI (**p < 0.01 vs NC) and AD (**p < 0.01 vs NC, ##p < 0.01 vs MCI), and correlated well with the mini-mental state examination (MMSE) score (r = 0.57, *p < 0.05). Furthermore, the eye tracking test, especially memory and deductive reasoning tasks, effectively discriminated NC, MCI and AD. The present novel eye tracking test clearly discriminated cognitive functions among NC, MCI, and AD subjects, thereby providing an advantage for the early detection of MCI and AD in screening.

DOI： 10.1016/j.jns.2021.117529

A case of rheumatoid meningoencephalitis induced by pembrolizumab

Chika Matsuoka, Yoshio Omote, Yuko Kawahara, Ryo Sasaki, Namiko Matsumoto, Ko Tadokoro, Yuki Taira, Mami Takemoto, Ryuta Morihara, Toru Yamashita, Koji Abe

NEUROLOGY AND CLINICAL NEUROSCIENCE 2021.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Immune checkpoint inhibitors occasionally cause various side effects, but the occurrence of a severe immune-related adverse event (irAE) is rare in neurology. We report on a 56-year-old woman who suffered from rheumatoid arthritis and recurrent uterine cancer. After treatment with pembrolizumab, she showed visual disturbance followed by acute fever and consciousness disturbance with high-intensity lesions around the midbrain aqueduct and bilateral caudate heads on FLAIR images of a brain MRI. Her symptoms improved after steroid therapy. However, symptoms relapsed leading to an elevation of the anti-CCP antibody index. Pembrolizumab-induced rheumatoid meningoencephalitis was suspected, so additional steroid therapy was provided. This improved her symptoms, turning the anti-CCP antibody index negative. The present case is the first case of rheumatoid meningoencephalitis induced by pembrolizumab. The combination of MRI findings and elevated anti-CCP index seems useful for diagnosing rheumatoid meningoencephalitis.

DOI： 10.1111/ncn3.12540

Switching the Proteolytic System from the Ubiquitin-Proteasome System to Autophagy in the Spinal Cord of an Amyotrophic Lateral Sclerosis Mouse Model. International journal

Koh Tadokoro, Toru Yamashita, Jingwei Shang, Yasuyuki Ohta, Emi Nomura, Ryuta Morihara, Yoshio Omote, Mami Takemoto, Koji Abe

Neuroscience 466 47 - 57 2021.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.

DOI： 10.1016/j.neuroscience.2021.04.034

The first case of chronic inflammatory demyelinating polyneuropathy after transsexualism and continuous testosterone administration

Yuki Taira, Yoshio Omote, Yuko Kawahara, Emi Nomura, Ryo Sasaki, Namiko Matsumoto, Chika Matsuoka, Mami Takemoto, Ryuta Morihara, Nozomi Hishikawa, Toru Yamashita, Koji Abe

NEUROLOGY AND CLINICAL NEUROSCIENCE 9 ( 4 ) 346 - 348 2021.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

We report on a 35-year-old man who had gender dysphoria following unilateral ovariectomy and then received continuous testosterone injection for nine years, inducing chronic inflammatory demyelinating polyneuropathy (CIDP). He developed recurrent muscle weakness and numbness in the extremities and displayed demyelinating neuropathy, detected by nerve conduction studies and a sural nerve biopsy. Repeated intravenous immunoglobulin (IVIg) therapy and the administration of oral prednisolone improved symptoms and inhibited their recurrence. A relatively high level of serum testosterone as a genetic female might have caused the neurotoxicity of the peripheral nerve, leading to CIDP.

DOI： 10.1111/ncn3.12514

4-Hydroxyl-2-Nonenal Localized Expression Pattern in Retrieved Clots is Associated with Large Artery Atherosclerosis in Stroke Patients. International journal

Yosuke Osakada, Toru Yamashita, Ryuta Morihara, Namiko Matsumoto, Ryo Sasaki, Koh Tadokoro, Emi Nomura, Yuko Kawahara, Yoshio Omote, Nozomi Hishikawa, Mami Takemoto, Yasuyuki Ohta, Yasuki Suruga, Takayuki Nagase, Yuji Takasugi, Satoshi Inoue, Kyoichi Watanabe, Kentaro Deguchi, Koji Tokunaga, Susumu Sasada, Kazuki Kobayashi, Ryosuke Maeoka, Kenji Fukutome, Kenkichi Takahashi, Hiroyuki Ohnishi, Yoshihiro Kuga, Hideyuki Ohnishi, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 30 ( 3 ) 105583 - 105583 2021.3

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The relationship between stroke etiology and clot pathology remains controversial. MATERIALS AND METHODS: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed. RESULTS: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots. CONCLUSIONS: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).

DOI： 10.1016/j.jstrokecerebrovasdis.2020.105583

Immediate Beneficial Effect of Makeup Therapy on Behavioral and Psychological Symptoms of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software. International journal

Koh Tadokoro, Toru Yamashita, Satoko Kawano, Junko Sato, Yoshio Omote, Mami Takemoto, Ryuta Morihara, Koichiro Nishiura, Natsuki Sagawa, Tomiko Tani, Koji Abe

Journal of Alzheimer's disease : JAD 83 ( 1 ) 57 - 63 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：IOS PRESS

BACKGROUND: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients. OBJECTIVE: To evaluate the immediate effect of makeup therapy on dementia patients. METHODS: Female nursing home residents with dementia received either only skin care treatment (control group, n = 17) or skin care plus makeup therapy treatment (makeup therapy group, n = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software. RESULTS: Makeup therapy significantly improved Abe's behavioral and psychological symptoms of dementia (BPSD) score (ABS, *p < 0.05). AI software judged that makeup therapy significantly made the apparent age younger (*p < 0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy (*p < 0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r = 0.42, *p < 0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy (*p < 0.05). CONCLUSION: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance.

DOI： 10.3233/JAD-210284

Retinal Amyloid Imaging for Screening Alzheimer's Disease. International journal

Koh Tadokoro, Toru Yamashita, Shuhei Kimura, Emi Nomura, Yasuyuki Ohta, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Ryuta Morihara, Yuki Morizane, Koji Abe

Journal of Alzheimer's disease : JAD 83 ( 2 ) 927 - 934 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：IOS PRESS

BACKGROUND: Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer's disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. OBJECTIVE: To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. METHODS: To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. RESULTS: Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. CONCLUSION: The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.

DOI： 10.3233/JAD-210327

Cerebral Microbleeds in Patients with Parkinson's Disease and Dementia with Lewy Bodies: Comparison Using Magnetic Resonance Imaging and 99 mTc-ECD SPECT Subtraction Imaging International journal

Mami Takemoto, Toru Yamashita, Yasuyuki Ohta, Koh Tadokoro, Yoshio Omote, Ryuta Morihara, Koji Abe

Journal of Alzheimer's disease : JAD 80 ( 1 ) 331 - 335 2021

Language：English Publishing type：Research paper (scientific journal) Publisher：IOS PRESS

BACKGROUND: Cerebral microbleeds (CMBs) in patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. OBJECTIVE: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 mTc-ECD SPECT subtraction images of these two diseases. METHODS: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 mTc-ECD SPECT subtraction imaging. RESULTS: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7-17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. CONCLUSION: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.

DOI： 10.3233/JAD-201495

Neuroprotective and Therapeutic Effects of Tocovid and Twendee-X on Aβ Oligomer-Induced Damage in the SH-SY5Y Cell Line. International journal

Xiao Hu, Toru Yamashita, Haibo Yu, Zhihong Bian, Xinran Hu, Tian Feng, Koh Tadokoro, Ryuta Morihara, Koji Abe

Neuro-degenerative diseases 21 ( 5-6 ) 117 - 125 2021

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Alzheimer's disease (AD) is the most frequent cause of dementia among the elderly. The accumulation of amyloid beta (Aβ) and its downstream pathological events such as oxidative stress play central roles in AD. Recent studies revealed that Aβ oligomer (AβO)-induced strong neurotoxicity in SH-SY5Y cells via the induction of oxidative stress. OBJECTIVE: In the present study, we investigated the effect of two antioxidants, Tocovid and Twendee-X, on AβO-induced SH-SY5Y cell damage. METHODS: AβOs (2.5 μM) were applied to induce cellular damage in the SH-SY5Y cell line. Cell viability following AβO toxicity, Tau protein phosphorylation, cell morphology, and intracellular reactive oxygen species were assayed with or without different concentrations of Tocovid or Twendee-X. RESULTS: Tocovid (60 μg/mL) and Twendee-X (150 μg/mL) significantly recovered cell viability from AβO toxicity (**p < 0.01, vs. control), attenuated Tau protein phosphorylation (**p < 0.01, vs. AβOs), improved cell morphology (**p < 0.01, vs. AβOs), and suppressed intracellular ROS (**p < 0.01, vs. AβOs) in SH-SY5Y cells. CONCLUSION: These findings suggest the neuroprotective and therapeutic potential of Tocovid and Twendee-X for AD treatment.

DOI： 10.1159/000523983

Bone Marrow Stromal Cell Transplantation Drives Molecular Switch from Autophagy to the Ubiquitin-Proteasome System in Ischemic Stroke Mice. Reviewed International journal

Koh Tadokoro, Yusuke Fukui, Toru Yamashita, Xia Liu, Keiichiro Tsunoda, Jingwei Shang, Ryuta Morihara, Yumiko Nakano, Feng Tian, Ryo Sasaki, Namiko Matsumoto, Emi Nomura, Xiaowen Shi, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 29 ( 5 ) 104743 - 104743 2020.5

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER

BACKGROUND: Bone marrow stromal cell (BMSC) transplantation is a promising therapeutic approach for cerebral ischemia, as it elicits multiple neuroprotective effects. However, it remains unclear how BMSC transplantation modulates the ubiquitin-proteasome system (UPS) and autophagy under cerebral ischemia. METHODS: In the present study, an intermediate level of cerebral ischemia (30 minutes) was chosen to examine the effect of BMSC transplantation on the molecular switch regulating UPS and autophagy. BMSC or vehicle was stereotactically injected into the penumbra 15 minutes after sham operation or transient middle cerebral artery occlusion (tMCAO). RESULTS: Thirty minutes of tMCAO artery occlusion significantly increased TUNEL-, ubiquitin-, and p62-positive cells (which peaked at 72 hours, 2 hours, and 2 hours after reperfusion, respectively) and ratios of both BAG3/BAG1 and LC3-II/LC3-I at 24 hours after reperfusion. However, intracerebral injection of BMSCs significantly reduced infarct volume and numbers of TUNEL- and p62-positive cells, and improved BAG3/BAG1 and LC3-II/LC3-I ratios. In addition, observed increases in ubiquitin-positive cells 2 hours after reperfusion were slightly suppressed by BMSC transplantation. CONCLUSIONS: These data suggest a protective role of BMSC transplantation, which drove the molecular switch from autophagy to UPS in a murine model of ischemic stroke.

DOI： 10.1016/j.jstrokecerebrovasdis.2020.104743

Molecular switching from ubiquitin-proteasome to autophagy pathways in mice stroke model. Reviewed International journal

Xia Liu, Toru Yamashita, Jingwei Shang, Xiaowen Shi, Ryuta Morihara, Yong Huang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 40 ( 1 ) 214 - 224 2020.1

Language：English Publishing type：Research paper (scientific journal)

The ubiquitin-proteasome system (UPS) and autophagy are two major pathways to degrade misfolded proteins that accumulate under pathological conditions. When UPS is overloaded, the degeneration pathway may switch to autophagy to remove excessive misfolded proteins. However, it is still unclear whether and how this switch occurs during cerebral ischemia. In the present study, transient middle cerebral artery occlusion (tMCAO) resulted in accelerated ubiquitin-positive protein aggregation from 0.5 h of reperfusion in mice brain after 10, 30 or 60 min of tMCAO. In contrast, significant reduction of p62 and induction of LC3-II were observed, peaking at 24 h of reperfusion after 30 and 60 min tMCAO. Western blot analyses showed an increase of BAG3 and HDAC6 at 1 or 24 h of reperfusion that was dependent on the ischemic period. In contract, BAG1 decreased at 24 h of reperfusion after 10, 30 or 60 min of tMCAO after double immunofluorescent colocalization of ubiquitin, HSP70, p62 and BAG3. These data suggest that a switch from UPS to autophagy occurred between 10 and 30 min of cerebral ischemia depending on the BAG1/BAG3 ratio and level of HDAC6.

DOI： 10.1177/0271678X18810617

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