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Targeting tau in Alzheimer's disease:from mechanisms to clinical therapy

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Neural Regeneration Research 2024年第7期19卷 1489-1498页

作者： Jinwang Ye Huali Wan Sihua Chen Gong-Ping Liu Shenzhen Key Laboratory of Marine Biotechnology and Ecology College of Life Sciences and OceanographyShenzhen UniversityShenzhenGuangdong ProvinceChina Department of Laboratory Medicine Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhouGuangdong ProvinceChina Co-innovation center of Neurodegeneration Nantong UniversityNantongJiangsu ProvinceChina Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain ScienceKey Laboratory of Ministry of Education of China and Hubei Province for Neurological DisordersTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Alzheimer’s disease is the most prevalent neurodegenerative disease affecting older *** features of Alzheimer’s disease include extra cellular aggregation of amyloid-βplaques and the accumulation of neurofibrillary tangles,fo rmed by tau protein,in the *** there are amyloid-β-ta rgeting therapies for the treatment of Alzheimer’s disease,these therapies are costly and exhibit potential negative side *** evidence suggests significant involvement of tau protein in Alzheimer’s disease-related *** an important microtubule-associated protein,tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal *** fact,clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-βin the *** therapeutic strategies targeting tau protein have begun to emerge,and are considered possible methods to prevent and treat Alzheimer’s ***,abnormalities in post-translational modifications of the tau protein,including aberrant phosphorylation,ubiquitination,small ubiquitin-like modifier(SUMO)ylation,acetylation,and truncation,contribute to its microtubule dissociation,misfolding,and subcellular *** causes mitochondrial damage,synaptic impairments,gliosis,and neuroinflammation,eventually leading to neurodegeneration and cognitive *** review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer’s disease and discusses tau-targeted treatment of Alzheimer’s disease.

关键词： acetylation Alzheimer’s disease cognitive deficits gliosis mitochondria damage neuroinflammation phosphorylation synaptic impairments tau tau immunotherapy

brain-wide activation involved in 15 mA transcranial alternating current stimulation in patients with first-episode major depressive disorder

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General Psychiatry 2024年第2期37卷 265-273页

作者： Jie Wang Wenfeng Zhao Huang Wang Haixia Leng Qing Xue Mao Peng Baoquan Min Xiukun Jin Liucen Tan Keming Gao Hongxing Wang Songjiang Hospital and Songjiang Research Institute Shanghai Key Laboratory of Emotions and Affective DisordersShanghai Jiao Tong University School of MedicineShanghaiChina Institute of Neuroscience and brain Diseases Xiangyang Central HospitalAffiliated Hospital of Hubei University of Arts and ScienceXiangyangHubeiChina Division of Neuropsychiatry and Psychosomatics Department of NeurologyXuanwu Hospital of Capital Medical UniversityBeijingChina Electroconvulsive Therapy University Hospitals Cleveland Medical CenterClevelandOhioUSA Department of Psychiatry Case Western Reserve University School of MedicineClevelandOhioUSA Institute of Sleep and Consciousness disorders Center of EpilepsyBeijing Institute for Brain DisordersCapital Medical UniversityBeijingChina Institute of Special Medical sciences School of Forensic MedicineShanxi Medical UniversityTaiyuanShanxiChina

Background Although 15 mA transcranial alternating current stimulation(tACS)has a therapeutic effect on depression,the activations of brain structures in humans accounting for this tACS configuration remain largely *** To investigate which intracranial brain structures are engaged in the tACS at 77.5 Hz and 15 mA,delivered via the forehead and the mastoid electrodes in the human *** Actual human head models were built using the magnetic resonance imagings of eight outpatient volunteers with drug-naïve,first-episode major depressive disorder and then used to perform the electric field distributions with SimNIBS *** The electric field distributions of the sagittal,coronal and axial planes showed that the bilateral frontal lobes,bilateral temporal lobes,hippocampus,cingulate,hypothalamus,thalamus,amygdala,cerebellum and brainstem were visibly stimulated by the 15 mA tACS *** brain-wide activation,including the cortex,subcortical structures,cerebellum and brainstem,is involved in the 15 mA tACS intervention for first-episode major depressive *** results indicate that the simultaneous involvement of multiple brain regions is a possible mechanism for its effectiveness in reducing depressive symptoms.

关键词： stimulation involvement activation

Deep learning-based optical aberration estimation enables offline digital adaptive optics and super-resolution imaging

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Photonics Research 2024年第3期12卷 474-484页

作者： CHANG QIAO HAOYU CHEN RUN WANG TAO JIANG YUWANG WANG DONG LI Department of Automation Tsinghua UniversityBeijing 100084China Institute for brain and cognitive sciences Tsinghua UniversityBeijing 100084China National Laboratory of Biomacromolecules New Cornerstone Science LaboratoryCAS Center for Excellence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China College of Life sciences University of Chinese Academy of SciencesBeijing 100049China Beijing National Research center for Information Science and Technology Tsinghua UniversityBeijing 100084China

Optical aberrations degrade the performance of fluorescence *** adaptive optics(AO)leverages specific devices,such as the Shack–Hartmann wavefront sensor and deformable mirror,to measure and correct optical ***,conventional AO requires either additional hardware or a more complicated imaging procedure,resulting in higher cost or a lower acquisition *** this study,we proposed a novel space-frequency encoding network(SFE-Net)that can directly estimate the aberrated point spread functions(PSFs)from biological images,enabling fast optical aberration estimation with high accuracy without engaging extra optics and image *** showed that with the estimated PSFs,the optical aberration can be computationally removed by the deconvolution ***,to fully exploit the benefits of SFE-Net,we incorporated the estimated PSF with neural network architecture design to devise an aberration-aware deeplearning super-resolution model,dubbed *** demonstrated that the combination of SFE-Net and SFT-DFCAN enables instant digital AO and optical aberration-aware super-resolution reconstruction for live-cell imaging.

关键词： optics resolution enable

Ethical concerns in aging research:perspectives of global frontline researchers

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Science China(Life sciences) 2024年第10期67卷 2149-2156页

作者： Yaojin Peng Lulu Ding Zhenyu Xiao Moshi Song Jianwei Lv Guang-Hui Liu Key Laboratory of Organ Regeneration and Reconstruction State Key Laboratory of Stem Cell and Reproductive BiologyInstitute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of sciences Beijing 100049China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Aging Biomarker Consortium(ABC) Beijing 100101China School of Life Science Beijing Institute of TechnologyBeijing 100081China School of Life sciences Xiamen UniversityXiamen 361102China Advanced Innovation center for Human brain Protection and National Clinical Research center for Geriatric disorders Xuanwu HospitalCapital Medical UniversityBeijing 100053China Aging Translational Medicine center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China

This study investigated the ethical landscape of aging research amid the increasing global focus on extending the human lifespan and health *** global survey of 180 researchers across 38 jurisdictions revealed divergent perceptions of aging,a consensus regarding the feasibility of delaying aging,and multiple perspectives regarding lifespan *** present findings underscore a paradigm shift toward inclusive and ethically sound research,emphasizing the need for an approach that strikes a balance between basic and clinical *** addition,this study highlighted key ethical concerns in aging research,including the effects of misleading advertising,potential inequality in access to aging interventions,and risks pertaining to the extrapolation of research findings from lower-model organisms to *** insights presented in this paper call for an integrated approach for overcoming the complex ethical and societal challenges in aging research to ensure responsible and equitable advancements in this burgeoning field.

关键词： aging ethical landscape ethics surveys and questionnaires

cognitive impairment in cerebral small vessel disease induced by hypertension

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Neural Regeneration Research 2024年第7期19卷 1454-1462页

作者： Weipeng Wei Denglei Ma Lin Li Lan Zhang Department of Pharmacy Xuanwu Hospital of Capital Medical UniversityBeijingChina Beijing Geriatric Medical Research center Beijing Engineering Research Center for Nervous System DrugsNational Center for Neurological DisordersNational Clinical Research Center for Geriatric DiseasesBeijingChina

Hypertension is a primary risk factor for the progression of cognitive impairment caused by cerebral small vessel disease,the most common cerebrovascular *** r,the causal relationship between hypertension and cerebral small vessel disease remains *** has substantial negative impacts on brain health and is recognized as a risk factor for cerebrovascular *** hypertension and lifestyle factors are associated with risks for stro ke and dementia,and cerebral small vessel disease can cause dementia and *** is the main driver of cerebral small vessel disease,which changes the structure and function of cerebral vessels via various mechanisms and leads to lacunar infarction,leukoaraiosis,white matter lesions,and intracerebral hemorrhage,ultimately res ulting in cognitive decline and demonstrating that the brain is the to rget organ of *** review updates our understanding of the pathogenesis of hypertensioninduced cerebral small vessel disease and the res ulting changes in brain structure and function and declines in cognitive *** also discuss drugs to treat cerebral small vessel disease and cognitive impairment.

关键词： blood-brain barrier cerebral small vessel disease cognitive impairment dementia endothelial dysfunction enlarged perivascular space hypertension lacunar infarction neuroinflammation treatment white matter high signal intensity

Caliper-based precise positioning of the target(CALIPPOT)for transcranial magnetic stimulation without neuronavigation system

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General Psychiatry 2024年第2期37卷 311-314页

作者： Yunsong Hu Rong Zeng Juan Yue Qiu Ge Hongxiao Wang Zijian Feng Jue Wang Yufeng Zang center for Cognition and brain disorders The Affiliated Hospital of Hangzhou Normal UniversityHangzhouZhejiangChina Zhejiang Key Laboratory for Research in Assessment of cognitive Impairments HangzhouZhejiangChina Institutes of Psychological sciences Hangzhou Normal UniversityHangzhouZhejiangChina Transcranial Magnetic Stimulation center Deqing Hospital of Hangzhou Normal UniversityDeqingZhejiangChina Institute of Sports Medicine and Health Chengdu Sport UniversityChengduSichuanChina Department of Neurology The Affiliated Hospital of Hangzhou Normal UniversityHangzhouZhejiangChina

To the editor:Transcranial magnetic stimulation(TMS)is a non-invasive brain modulation *** important usage of TMS is the transient interruption of cognitive brain function(also named virtual lesion)for investigating precisely where and when a specific cortical region contributes to a specific cognitive function.1 A more important usage of TMS is the treatment of brain disorders by repetitive TMS(rTMS).

关键词： stimulation technique. precise

Identification of FOXO1 as a geroprotector in human synovium through single-nucleus transcriptomic profiling

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Protein & Cell 2024年第6期15卷 441-459页

作者： Feifei Liu Yi Lu Xuebao Wang Shuhui Sun Huize Pan Min Wang Zehua Wang Weiqi Zhang Shuai Ma Guoqiang Sun Qun Chu Si Wang Jing Qu Guang-Hui Liu State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Sports Medicine Department Beijing Jishuitan HospitalCapital Medical UniversityBeijing 100035China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of sciences Beijing 100049China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101China National Laboratory of Biomacromolecules Institute of BiophysicsChinese Academy of SciencesBeijing 100101China Division of Life sciences and Medicine School of Life SciencesUniversity of Science and Technology of ChinaHefei 230001China CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijing 100101China The Fifth People’s Hospital of Chongqing Chongqing 400062China Advanced Innovation center for Human brain Protection and National Clinical Research center for Geriatric disorders Xuanwu Hospital Capital Medical UniversityBeijing 100053China Aging Translational Medicine center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China

The synovium,a thin layer of tissue that is adjacent to the joints and secretes synovial fluid,undergoes changes in aging that contribute to intense shoulder pain and other joint ***,the mechanism underlying human synovial aging remains poorly ***,we generated a comprehensive transcriptomic profile of synovial cells present in the subacromial synovium from young and aged *** delineating aging-related transcriptomic changes across different cell types and their associated regulatory networks,we identified two subsets of mesenchymal stromal cells(MSCs)in human synovium,which are lining and sublining MSCs,and found that angiogenesis and fibrosis-associated genes were upregulated whereas genes associated with cell adhesion and cartilage development were downregulated in aged ***,the specific cell-cell communications in aged synovium mirrors that of aging-related inflammation and tissue remodeling,including vascular hyperplasia and tissue *** particular,we identified forkhead box O1(FOXO1)as one of the major regulons for aging differentially expressed genes(DEGs)in synovial MSCs,and validated its downregulation in both lining and sublining MSC populations of the aged *** human FOXO1-depleted MSCs derived from human embryonic stem cells,we recapitulated the senescent phenotype observed in the subacromial synovium of aged *** data indicate an important role of FOXO1 in the regulation of human synovial ***,our study improves our understanding of synovial aging during joint degeneration,thereby informing the development of novel intervention strategies aimed at rejuvenating the aged joint.

关键词： FOXO1 degeneration inflammation

Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation

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National Science Review 2024年第6期11卷 119-128页

作者： Chunyu Zhao Jia Tu Chuchu Wang Wenbin Liu Jinge Gu Yandong Yin Shengnan Zhang Dan Li Jiajie Diao Zheng-Jiang Zhu Cong Liu Interdisciplinary Research center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences University of Chinese Academy of sciences Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders Ministry of Education Shanghai Jiao Tong University Zhangjiang Institute for Advanced Study Shanghai Jiao Tong University Department of Cancer Biology University of Cincinnati College of Medicine

Accumulation of aggregated α-synuclein(α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease(PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids(LPLs),particularly targeting lysophosphatidylcholine(LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

关键词： α-synuclein Parkinson's disease lysophosphatidylcholine, aggregation

STON2风险变异通过影响Syt1转运和突触功能导致精神分裂症样行为

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Science Bulletin 2024年第10期69卷 1458-1471页

作者：马远林高凯孙晓璇王金鑫杨扬武建荧柴安平姚立刘楠郁昊苏怡卢天兰王力芳岳伟华章晓辉徐林张岱李俊 Peking University Sixth Hospital Peking University Institute of Mental HealthNHC Key Laboratory of Mental Health(Peking University)National Clinical Research Center for Mental Disorders(Peking University Sixth Hospital)Key Laboratory of Mental HealthChinese Academy of Medical SciencesBeijing 100191China The First Affiliated Hospital Chongqing Medical UniversityChongqing Key Laboratory of NeurologyChongqing 400016China Changping Laboratory Beijing 102206China d Chinese Institute for brain Research Beijing 102206China Laboratory of Learning and Memory Kunming Institute of ZoologyChinese Academy of SciencesKunming 650201China Shenzhen Key Laboratory of Translational Research for brain Diseases The Brain Cognition and Brain Disease InstituteShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research InstitutionsShenzhen 518055China State Key Laboratory of cognitive Neuroscience and Learning IDG/McGovern Institute for Brain ResearchBeijing Normal UniversityBeijing 100875China PKU-IDG/McGovern Institute for brain Research Peking UniversityBeijing 100871China

Synaptic dysfunction is a core component of the pathophysiology of ***,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully *** Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic *** this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of *** found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for ***2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like ***,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)*** recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin *** findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.

关键词： STON2 variations Schizophrenia Synaptic dysfunction Syt1 Haloperidol