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Human stem cell-derived microglia will be an indispensable toolbox for Alzheimer's disease research

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Neural Regeneration Research 2021年第9期16卷 1770-1771页

作者： Tongfei Liu Neuroscience Initiative Sanford Burnham Prebys Medical Discovery InstituteLa JollaCAUSA Department of Biology Southern University of Science and TechnologyShenzhenGuangdong ProvinceChina

Alzheimer's disease(AD) is the most common age-related dementia without cures. Between 2000 and 2017, deaths resulting from AD increased 145%. Based on the latest statistical data, more than 50 million people in the world suffered this devastating disease, which is one of major burdens in modern public health system(Alzheimer's Association, 2020).

关键词： Alzheimer Human indispensable

Tissue inhibitors of metalloproteases strike a nerve

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Neural Regeneration Research 2018年第11期13卷 1890-1892页

作者： veronica i.shubayev alex y.strongin department of anesthesiology university of californiasan diego va san diego healthcare system la jollacausa sanford burnham prebys medical discovery institute la jollacausa

Signals of touch,pressure,pain,temperature,position,and vibration are transmitted from the peripheral nervous system（PNS）to the dorsal horn of the segmental spinal cord via pseudounipolar dorsal root ganglia（DRG）*** information gathering relies on functional integrity of DRG neurons and can be interrupted by PNS injury due to trauma,disease or exposure to drugs, toxins or viral pathogens. Despite the high regenerative capacity of DRG neurons, sensory recovery after PNS injury is often incomplete and severe neuropathic pain may last for years. Although numerous mechanisms of PNS injury have been established, neuropathic pain is refractory to therapy, contributing to the physical and emotional suffering of patients and the enormous economic burden to society.

关键词： TIMPs PNS In Tissue inhibitors of metalloproteases strike a nerve

Amyloid,tau,pathogen infection and antimicrobial protection in Alzheimer’s disease-conformist,nonconformist,and realistic prospects for AD pathogenesis

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Translational Neurodegeneration 2018年第1期7卷 362-377页

作者： Hongmei Li Chia-Chen Liu Hui Zheng Timothy Y.Huang Department of Neuroscience Mayo ClinicJacksonvilleFLUSA Huffington Center on Aging Baylor College of MedicineHoustonTXUSA Neuroscience Initiative Sanford Burnham Prebys Medical Discovery InstituteSan DiegoCAUSA

Background:Alzheimer’s disease(AD)is a fatal disease that threatens the quality of life of an aging population at a global *** hypotheses on the etiology of AD have been developed over the years to guide efforts in search of therapeutic *** body:In this review,we focus on four AD hypotheses currently relevant to AD onset:the prevailing amyloid cascade hypothesis,the well-recognized tau hypothesis,the increasingly popular pathogen(viral infection)hypothesis,and the infection-related antimicrobial protection *** briefly reviewing the main evidence supporting each hypothesis and discussing the questions that need to be addressed,we hope to gain a better understanding of the complicated multi-layered interactions in potential causal and/or risk factors in AD *** a defining feature of AD,the existence of amyloid deposits is likely fundamental to AD onset but is insufficient to wholly reproduce many complexities of the disorder.A similar belief is currently also applied to hyperphosphorylated tau aggregates within neurons,where tau has been postulated to drive neurodegeneration in the presence of pre-existing Aβplaques in the *** infection of the central nerve system by pathogens such as viruses may increase AD risk,it is yet to be determined whether this phenomenon is applicable to all cases of sporadic AD and whether it is a primary trigger for AD ***,the antimicrobial protection hypothesis provides insight into a potential physiological role for Aβpeptides,but how Aβ/microbial interactions affect AD pathogenesis during aging awaits further ***,this hypothesis cautions potential adverse effects in Aβ-targeting therapies by hindering potential roles for Aβin anti-viral ***:AD is a multi-factor complex disorder,which likely requires a combinatorial therapeutic approach to successfully slow or reduce symptomatic memory decline.A better understanding of how various causal a

关键词： Amyloid-beta Alzheimer’s disease Amyloid hypothesis Tau hypothesis Pathogen hypothesis Viral infection Antimicrobial protection

Bidirectional modulation of HIF-2 activity through allosteric ligands

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中国药理学与毒理学杂志 2019年第10期 767-768页

作者： WU Da-lei SU Xiao-yu LU Jing-ping LI Sheng Becky HOOD Stefan VASILE Nalini POTLURI DIAO Xiao-tong Young-chang KIM Sepideh KHORASANIZADEH Fraydoon RASTINEJAD State Key Laboratory of Microbial Technology Shandong University sanford burnham prebys medical discovery institute 3. Department of Medicine University of California San Diego 4. Argonne National Laboratory 5. Nuffield Department of Medicine University of Oxford

OBJECTIVE Hypoxia-inducible factor-2(HIF-2) is a heterodimeric transcription factor formed through dimerization between an oxygen-sensitive subunit HIF-2α subunit and its obligate partner subunit *** HIF-2 activity drives some cancers, while reduced activity causes anemia in chronic kidney disease. Therefore, modulation of HIF-2 activity via direct-binding ligands could provide many new therapeutic benefits. METHODS We explored HIF-2α chemical ligands using combined crystallographic, biophysical, and cell-based functional studies. RESULTS We found chemically unrelated antagonists to employ the same mechanism of *** binding displaced residue M252 from inside the HIF-2α PAS-B pocket toward the ARNT subunit to weaken heterodimerization. We also identified first-in-class HIF-2α agonists and found they significantly displaced pocket residue Y281. Its dramatic side-chain movement increases heterodimerization stability and transcriptional *** Our findings show that despite binding to the same HIF-2α PAS-B pocket, ligands can manifest as inhibitors versus activators by mobilizing different pocket residues to al osterical y alter HIF-2α-ARNT heterodimerization.

关键词： hypoxia-inducible factor agonist antagonist allosteric effects

Role of myelin auto-antigens in pain:a female connection

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Neural Regeneration Research 2016年第6期11卷 890-891页

作者： Veronica I.Shubayev Alex Y.Strongin Tony L.Yaksh Department of Anesthesiology University of CaliforniaSan DiegoLa JollaCAUSA VA San Diego Healthcare System La JollaCAUSA sanford-burnham-prebys medical discovery institute La jollaCAUSA

Following injury to the peripheral nerve,pain secondary to low threshold innocuous mechanical stimulation（mechanical allodynia）is commonly *** origins are poorly understood and the pain is often refractory to common analgesic *** past two decades has brought major advances in our understanding of the complexity of systems that underlie processing of neuropathic pain（pain arising from damage or disease of the somatosensory system）.

关键词： myelin understood stimulation poorly refractory analgesic microglia immunity signaling likely

Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer＇s Disease

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Chinese medical Journal 2017年第24期130卷 2978-2990页

作者： Xi-Lin Wu Juan Pina-Crespo Yun-Wu Zhang Xiao-Chun Chen Hua-Xi Xu Neuroscience Initiative Neuroscience and Aging Research Center Sanford Burnham Prebys Medical Discovery Institute La Jolla CA 92037 USA Department of Neurology Fujian Institute of Geriatrics Fujian Medical University Union Hospital Fujian Key Laboratory of Molecular Neurology Fujian Medical University Fuzhou Fujian 350001 China Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience College of Medicine Xiamen University XiamenFujian 361102 China

Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD *** Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google *** Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational *** articles were carefully reviewed,with no exclusions applied to study design and publication ***：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks *** the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD *** research focus in AD has recently shifted to the role oftau in *** addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological *** evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD *** to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the *** advances have potential to accurately determine tau levels at early diagnostic stages in *** that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD ***：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.

关键词： Alzheimer's Disease Biomarker lmmunotherapy Tau Imaging Tau Protein Transcellular Propagation

Cytoplasmic DNA: sources, sensing, and role in aging and disease

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四川生理科学杂志 2024年第4期46卷 89-89页

作者： Karl N Miller Aging Cancer and Immuno-oncology Program Sanford Burnham Prebys Medical Discovery Institute La Jolla CA 92037 USA Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN 55905 USA Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN 55905 USA institute for Cell and Molecular Biosciences & Newcastle University institute for Ageing Newcastle upon Tyne NE4 5PL UK International institute of Molecular Mechanisms and Machines Polish Academy of Sciences 02-109 Warsaw Poland

Endogenous cytoplasmic DNA(cytoDNA)species are emerging as key mediators of inflammation in diverse physiological and pathological *** the role of endogenous cytoDNA in innate immune activation is well established,the cytoDNA species themselves are often poorly characterized and difficult to distinguish,and their mechanisms of formation,scope of function and contribution to disease are incompletely understood.

关键词： endogenous inflammation incomplete

马传染性贫血病毒拮抗马属动物天然免疫限制因子SAMHD1的分子机制研究

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中国预防兽医学报 2020年第12期42卷 1308-1308页

作者： REN HUI-LING YIN XIN SU CHAO State Key Laboratory of Veterinary Biotechnology Harbin Veterinary Research Institute the Chinese Academy of Agricultural Sciences Harbin China.

SAMHD1因被发现可以限制人免疫缺陷病毒-1型(HIV-1)的复制而引起人们的广泛关注。SAMHD1是一种脱氧核糖核苷三磷酸(dNTPs)水解酶(dNTPase),通过水解细胞内的dNTPs,将其维持在病毒反转录所需的浓度以下,从而限制逆转录病毒的复制。在巨... 详细信息

SAMHD1因被发现可以限制人免疫缺陷病毒-1型(HIV-1)的复制而引起人们的广泛关注。SAMHD1是一种脱氧核糖核苷三磷酸(dNTPs)水解酶(dNTPase),通过水解细胞内的dNTPs,将其维持在病毒反转录所需的浓度以下,从而限制逆转录病毒的复制。在巨噬细胞中,SAMHD1这一生物学功能使得HIV-1不能在其中有效复制。与HIV-1不同,HIV-2和一些猴免疫缺陷病毒(SIV)编码的Vpx蛋白可招募宿主的E3泛素连接酶CRL4DCAF1,特异性泛素化SAMHD1,使之通过蛋白酶体途径降解进而拮抗SAMHD1的限制作用。

关键词：马传染性贫血病毒马属动物限制因子逆转录病毒天然免疫巨噬细胞拮抗