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Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation

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Chinese Medical Sciences Journal 2022年第4期37卷 320-330页

作者： Ran Li Zhanyun Lv Yanxin Li Wei Li Yanlei Hao School of Basic Medical Sciences Shandong UniversityJinan 250012China Zhejiang University Medical Center Hangzhou 311121China department of neurology Pingdu People’s HospitalQingdaoShandong 266799China department of neurology Affiliated Hospital of Jining Medical CollegeJiningShandong 272007China

Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E *** A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of *** the mice were sacrificed,the hippocampus was excised for further *** was used to identify the cell that expresses TYROBP and the number of microglia and *** blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory *** Our results showed that TYROBP specifically expressed in the microglia of mouse *** of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of ***,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.

关键词： TYRO protein kinase-binding protein PSEN1 p.G378E mutation Tau phosphorylation neuroinflammation microglia cells astrocytes Alzheimer's disease

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Identification of Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease

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Chinese Medical Journal 2018年第4期131卷 448-453页

作者： Hua-Xu Liu Chuan-Qiang Pu Qiang Shi Yu-Tong Zhang Rui Ban department of neurology Chinese People's Liberation Army General Hospital Beijing 100853 China School of Medicine Nankai University Tianjin 300071 China

Background： Pompe disease is a rare lysosomal glycogen storage disorder linked to the acid alpha-glucosidase gene （GAA）. A wide clinical and genetic variability exists between patients from different ethnic populations, and the genotype-phenotype correlations are still not well understood. The aim of this study was to report the clinicopathological and genetic characteristics of five Chinese patients with late-onset Pompe disease （LOPD） who carried novel GAA gene mutations. Methods： Clinical and pathological data of patients diagnosed with glycogen storage disease at our institution from April 1986 to August 2017 were collected, and next-generation sequencing of frozen muscle specimens was conducted. Results： Of the five patients included in the study, the median disease onset age was 13 years, with a median 5 years delay in diagnosis. The patients mainly manifested as progressive weakness in the proximal and axial muscles, while one patient developed respiratory insufficiency that required artificial ventilation. In muscle biopsies, vacuoles with variable sizes and shapes appeared inside muscle fibers, and they stained positive for both periodic acid-Schiff and acid phosphatase staining. Ten GAA gene mutations, including seven novel ones （c.796C〉A, c. 1057C〉T, c. 1201C〉A, c. 1780C〉T, c. 1799G〉C, c.2051C〉A, c.2235dupG）, were identified by genetic tests. Conclusions： The seven novel GAA gene mutations revealed in this study broaden the genetic spectrum of LOPD and highlight the genetic heterogeneity in Chinese LOPD patients.

关键词： Alpha-glucosidase DNA Mutational Analysis Genetic Heterogeneity Glycogen Storage Disease Type Ⅱ

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Advantages of Rho-associated kinases and their inhibitor fasudil for the treatment of neurodegenerative diseases

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Neural Regeneration Research 2022年第12期17卷 2623-2631页

作者： Qing Wang Li-Juan Song Zhi-Bin Ding Zhi Chai Jie-Zhong Yu Bao-Guo Xiao Cun-Gen Ma Research Center of Neurobiology The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese MedicineShanxi University of Chinese MedicineJinzhongShanxi ProvinceChina department of Physiology Shanxi Medical UniversityTaiyuanShanxi ProvinceChina Institute of Brain Science Shanxi Key Laboratory of Inflammatory Neurodegenerative DiseasesShanxi Datong UniversityDatongShanxi ProvinceChina department of neurology Datong Fifth People’s HospitalDatongShanxi ProvinceChina Institute of neurology Huashan HospitalInstitutes of Brain Science and State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina

Ras homolog(Rho)-associated kinases(ROCKs)belong to the serine-threonine kinase family,which plays a pivotal role in regulating the damage,survival,axon guidance,and regeneration of *** are also involved in the biological effects of immune cells and glial cells,as well as the development of neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and multiple *** studies by us and others confirmed that ROCKs inhibitors attenuated the symptoms and progression of experimental models of the abovementioned neurodegenerative diseases by inhibiting neuroinflammation,regulating immune imbalance,repairing the blood-brain barrier,and promoting nerve repair and myelin ***,the first ROCKs inhibitor to be used clinically,has a good therapeutic effect on neurodegenerative *** increases the activity of neural stem cells and mesenchymal stem cells,thus optimizing cell *** review will systematically describe,for the first time,the effects of abnormal activation of ROCKs on T cells,B cells,microglia,astrocytes,oligodendrocytes,and pericytes in neurodegenerative diseases of the central nervous system,summarize the therapeutic potential of fasudil in several experimental models of neurodegenerative diseases,and clarify the possible cellular and molecular mechanisms of ROCKs *** review also proposes that fasudil is a novel potential treatment,especially in combination with cell-based *** from this review add support for further investigation of ROCKs and its inhibitor fasudil for the treatment of neurodegenerative diseases.

关键词： Alzheimer’s disease cell-based therapy central nervous system cells fasudil immunocytes multiple sclerosis Parkinson’s disease pericytes Rho kinase inhibitor Rho-associated kinases

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Association of variants in the KIF1A gene with amyotrophic lateral sclerosis

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Translational Neurodegeneration 2022年第1期11卷 235-247页

作者： Panlin Liao Yanchun Yuan Zhen Liu Xiaorong Hou Wanzhen Li Jin Wen Kexuan Zhang Bin Jiao Lu Shen Hong Jiang Jifeng Guo Beisha Tang Zhuohua Zhang Zhonghua Hu Junling Wang Hunan Key Laboratory of Molecular Precision Medicine Department of Critical Care MedicineXiangya HospitalCentral South UniversityChangsha 410008China department of neurology Xiangya HospitalCentral South UniversityChangsha 410008China National Clinical Research Center for Geriatric Diseases Xiangya HospitalCentral South UniversityChangsha 410008China Key Laboratory of Hunan Province in Neurodegenerative disorders Central South UniversityChangsha 410008China Center for Medical Genetics School of Life SciencesCentral South UniversityChangsha 410008China Engineering Research Center of Hunan Province in Cognitive Impairment disorders Central South UniversityChangsha 410008China Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases Changsha 410008China Hunan Provincial Clinical Research Center for Critical Care Medicine Xiangya HospitalCentral South UniversityChangsha 410008China Hunan Key Laboratory of Animal Models for Human Diseases School of Life SciencesCentral South UniversityChangsha 410008China.

Background:Amyotrophic lateral sclerosis(ALS)is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal *** in many other neurodegenerative disorders,the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal ***,sen-sory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2(HSAN2)and spastic paraplegia 30(SPG30)share several causative genes with ALS,as well as having common clinical ***1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors(SVPs)and dense core vesicles and has been reported as a causative gene for HSAN2 and ***:Here,we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ***:We identified rare damage variants(RDVs)in the KIF1A gene associated with ALS and delineated the clini-cal characteristics of ALS patients with KIF1A ***,these patients tended to exhibit sensory ***,the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A *** examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A,VAMP2,and *** of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A ***:Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS,indicating KIF1A as an important player in the oligogenic scenario of ALS.

关键词： Amyotrophic lateral sclerosis KIF1A Axonal transport Presynaptic vesicle precursors

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Soluble alpha-synuclein post-translational modifications:unexpected regulators of pathological alpha-synuclein amplification

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Neural Regeneration Research 2024年第5期19卷 959-960页

作者： Simran Kapila Yuhan Sun Chao Peng Shujing Zhang department of neurology David Geffen School of MedicineUniversity of CaliforniaLos AngelesCAUSA Molecular Biology Institute Brain Research InstituteMary S.Easton Center for Alzheimer’s ResearchUniversity of CaliforniaLos AngelesCAUSA

The build-up of misfoldedα-synuclein(α-syn)in the central nervous system is the pathological hallmark of a number of neurodegenerative diseases that are known asα-*** include Parkinson’s disease(PD),Parkinson’s disease with dementia(PDD),dementia with Lewy body(LB),multiple system atrophy(MSA),and a subset of Alzheimer’s *** evidence underscores that the intercellular transmission and amplification of pathologicalα-syn are critical processes underlying the progression ofα-synucleinopathies(Peng et al.,2020),and as such,the study of these processes could lead to the identification of promising therapeutics to mitigate disease *** previous studies have focused solely on pathological seeds in relation to disease progression.

关键词： pathological diseases

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POEMS syndrome associated with Castleman disease:a case report and literature review

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Neuroimmunology and Neuroinflammation 2014年第1期1卷 40-43页

作者： Juan Kang Fang Yang Hong‑Ya Zhang Meng‑Meng Hu Feng Xia Jin‑Cun Wang Yan‑Chun Deng Gang Zhao department of neurology Xijing HospitalFourth Military Medical UniversityXi’an 710032ShaanxiChina

Polyneuropathy,organomegaly,endocrinopathy,M proteins,and skin changes(POEMS)syndrome is a multisystemic disorder that clinically manifests as paraneoplastic and monoclonal plasma cell *** acronym is derived from its principal characteristics:polyneuropathy,organomegaly,endocrinopathy,M proteins,and skin ***,the authors reported a case of POEMS syndrome that was also associated with Castleman disease.A 53-year-old female patient was admitted to our hospital with limb weakness,numbness,edema,abdominal distention,and *** examination revealed tetraplegia,paraesthesia,and hyporeflexia in all four limbs,in addition to lymphadenectasis,splenomegaly,skin hyperpigmentation,hypertrichosis,and pitting *** tests and imaging revealed thrombocytosis,hypothyroidism,diabetes,hydropericardium,hydrothorax,splenomegaly,and *** showed the characteristic patterns of both demyelinating disease and axonal *** protein electrophoresis revealed monoclonal immunoglobulin G-lambda *** examination clearly diagnosed the disease as the hyaline vascular *** final diagnosis in this case was POEMS syndrome in association with Castleman disease.

关键词： Castleman disease hyaline vascular variant M protein polyneuropathy POEMS syndrome

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Multiple sclerosis:why we should focus on both sides of the(auto)antibody

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Neural Regeneration Research 2021年第12期16卷 2422-2424页

作者： Jeroen den Dunnen Lynn Mes Willianne Hoepel Joost Smolders Amsterdam Rheumatology and Immunology Center Department of Rheumatology and Clinical ImmunologyDepartment of Experimental ImmunologyAmsterdam Institute for Infection and ImmunityAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands department of Medical Microbiology Amsterdam institute for Infection and ImmunityAmsterdam UMCUniversity of AmsterdamAmsterdamThe Netherlands(Mes L)Neuroimmunology Research groupNetherlands Institute for NeuroscienceAmsterdamMS Center ErasMSDepartments of Neurology and ImmunologyErasmus Medical CenterRotterdamThe Netherlands

Various clinical and experimental findings suggest a pathogenic role of antibodies in multiple sclerosis(MS).Yet,whether antibodies contribute to the pathogenesis or progression of MS is still a subject of intense *** controversy particularly results from unclarity regarding the target antigens of the antibodies that are found in the central nervous system(CNS)of MS patients.

关键词： sclerosis antibodies clinical

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SmartFlare^(TM) is a reliable method for assessing mRNA expression in single neural stem cells

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World Journal of Stem Cells 2021年第12期13卷 1918-1927页

作者： Andrea Diana Maria Dolores Setzu Zaal Kokaia Roxana Nat Cristina Maxia Daniela Murtas department of Biomedical Sciences University of CagliariMonserrato 09042CagliariItaly Laboratory of Stem Cells&Restorative neurology Lund Stem Cell CenterLund UniversityLund SE-22184LundSweden Institute of Neuroscience Medical University of InnsbruckInnsbruck 6020Austria

BACKGROUND One of the most challenging tasks of modern biology concerns the real-time tracking and quantification of mRNA expression in living *** this matter,a novel platform called SmartFlare^(TM) has taken advantage of fluorophore-linked nanoconstructs for targeting RNA *** fluorescence emission does not account for the spatial mRNA distribution,NanoFlare technology has grown a range of theranostic applications starting from detecting biomarkers related to diseases,such as cancer,neurodegenerative pathologies or embryonic developmental *** To investigate the potential of SmartFlare^(TM) in determining time-dependent mRNA expression of prominin 1(CD133)and octamer-binding transcription factor 4(OCT4)in single living cells through *** Brain fragments from the striatum of aborted human fetuses aged 8 wk postconception were processed to obtain *** the in vitro differentiation,neurospheres were gently dissociated with Accutase *** cells were resuspended in a basic medium enriched with fetal bovine serum,plated on poly-L-lysine-coated glass coverslips,and grown in a lapse of time from 1 to 4 *** cell mRNA detection was performed using SmartFlare^(TM) probes(CD133,Oct4,Actin,and Scramble).All the samples were incubated at 37°C for 24 *** nuclear staining,Hoechst 33342 was ***^(TM) CD133-and OCT4-specific fluorescence signal was assessed using a semiquantitative visual approach,taking into account the fluorescence intensity and the number of labeled *** In agreement with previous PCR experiments,a unique expression trend was observed for CD133 and OCT4 genes until 7 d in vitro(DIV).Fluorescence resulted in a mixture of diffuse cytoplasmic and spotted-like pattern,also detectable in the contacting neural *** 15 to 30 DIV,only few cells showed a scattered fluorescent pattern,in line with the differentiation progression and coherent with mRNA downregulation of

关键词： mRNA detection SmartFlareTM NanoFlare Live staining Nanotechnology Neural stem cell genes

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Aortic Plaque as a Potential Cause for Cerebral Ischemia

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Journal of Huazhong University of Science and Technology(Medical Sciences) 1997年第3期17卷 177-181页

作者：郭毅 department of Neurosurgery Shenzhen People’s Hospital Shenzhen departments of neurology and Cardiology Ernst-Moritz-Arndt University Germany

The purpose of this study was to determine the prevalence, clinical significance, and embolic potential of thoracic aortic plaque in patients with cerebral ischemia and to further study the correlation of aortic plaque with carotid or heart disease. We used transesophageal echography (TEE) to evaluate potential source of emboli in aortic arch and heart, and duplex in carotid artery. A atherosclerotic lesion of aortic arch was defined as normal (0), mild plaque (1), moderate plaque (2) and protruding plaque or mobile plaque (3). 75 of 100 patients were found to have atherosclerotic lesion in aortic arch. 16 of 75 patients over degree 2 exhibited no pathologic finding of heart or carotid and 4 of 16 patients were classified as degree 3. The pathologic findings of heart and carotid were significantly correlated with aortic plaque. Age, diabetes, CAD were also significantly correlated with aortic plaque. Aortic atherosclerosis was common in cerebral ischemia. Aortic plaque might be responsible for not only some unexplained embolic events, but also for some of the embolic stroke in patient who have carotid artery or heart disease. Age, diabetes, CAD might be important risk factors in the development of atherosclerotic lesion in the aortic arch.

关键词： embolism cerebral ischemia echocardiography

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ICH-induced inflammatory response upregulats hepcidin expression inhibits brain iron clearance and its mechanism

ICH-induced inflammatory response upregulats hepcidin expres...

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中国神经科学学会第十二届全国学术会议

作者： Xiong XY Liu L Wang FX Yang YR Hao JW Wang PF Zhong Q Zhou K Xiong A Zhu WY Zhao T Meng ZY Wang YC Gong QW Liao MF Wang J Yang QW department of neurology Xinqiao Hospital Third Military Medical University department of neurology Key Laboratory of Neurorepair and Regeneration Tianjin and Ministry of Education Tianjin Neurological Institute Tianjin Medical University General Hospital department of neurology Weihai Municipal Hospital department of Anesthesiology/Critical Care Medicine School of Medicine Johns Hopkins University

Objective Reducing the deposited brain iron is one of important measures in treatment of intracerebral hemorrhage（ICH）. Currently, as the mechanism of brain iron metabolism and its regulating and controlling factors after ICH are not clear, the effect of the treatment of reducing iron simply by physical method has larger difference. So exploring the mechanism of brain iron metabolism following ICH and giving the targeted intervention have important roles in the ICH therapy. Methods Parabiosis and ICH models combined with in vivo and in vitro experiments were used to investigate the roles of hepcidin in brain iron metabolism after ICH. Results After ICH, hepcidin-25 was found in serum and primarily in astrocytes. As human hepcidin-25 peptide injected into WT ICH mice, which aggravated the brain iron efflux, oxidative brain injury, and cognition impairment, but not in Hepc-/-ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited the intracellular iron efflux of brain microvascular endothelial cells but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. In addition, Toll-like receptor 4（TLR4）/My D88 signaling pathway increased hepcidin expression by promoting interleukin-6 expression and signal transducer and activator of transcription 3 phosphorylation. TLR4-/-and My D88-/-mice exhibited improvement in brain iron efflux at 7, 14, and 28 days after ICH, and the TLR4 antagonist（6 R）-6-[N-（2-chloro-4-fluorophenyl） sulfamoyl] cyclohex-1-ene-1-carboxylate significantly decreased brain iron levels at days 14 and 28 after ICH and improved cognition impairment at day 28. Conclusion This study further elucidate the mechanism of brain iron metabolism after ICH, and found TLR4 inhibitors could improve the effect of ICH treatment via inhibiting the hepcidin expression to reduce the deposited brain *** is expected to provide new methods for the tre

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