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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao michael S.Wolfe Computational Medicine Program and Department of Pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

NECAB family of neuronal calcium-binding proteins in health and disease

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Neural Regeneration Research 2025年第5期20卷 1236-1243页

作者： Diones Bueno michael K.E.Schafer Sudena Wang michael J.Schmeisser Axel Methner Institute for Molecular Medicine University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Department of Anesthesiology University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Institute of Anatomy University Medical Center of the Johannes Gutenberg-UniversityMainzGermany

The N-terminal EF-hand calcium-binding proteins 1–3(NECAB1–3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one EF-hand calcium-binding domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members were initially discovered due to their interactions with other proteins. NECAB1 associates with synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NECAB2 interacts with predominantly striatal G-protein-coupled receptors, while NECAB3 partners with amyloid-β A4 precursor protein-binding family A members 2 and 3, key regulators of amyloid-β production. This demonstrates the capacity of the family for interactions with various classes of proteins. NECAB proteins exhibit distinct subcellular localizations: NECAB1 is found in the nucleus and cytosol, NECAB2 resides in endosomes and the plasma membrane, and NECAB3 is present in the endoplasmic reticulum and Golgi apparatus. The antibiotic biosynthesis monooxygenase domain, an evolutionarily ancient component, is akin to atypical heme oxygenases in prokaryotes but is not wellcharacterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxygenase domains typically form dimers, suggesting that calcium-mediated conformational changes in NECAB proteins may induce antibiotic biosynthesis monooxygenase domain dimerization, potentially activating some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational changes might influence protein interactions or the subcellular localization of NECAB proteins by controlling the availability of protein–protein interaction domains situated between the EF hands and the antibiotic biosynthesis monooxygenase domain. This review summarizes what is known about genomic organization, tissue expression, intracellular localization, interac

关键词： calcium EF hand mitochondria nervous system signal transduction

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

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Neural Regeneration Research 2025年第1期20卷 224-233页

作者： Yi Zhang Zhongwu Liu michael Chopp michael Millman Yanfeng Li Pasquale Cepparulo Amy Kemper Chao Li Li Zhang Zheng Gang Zhang Department of Neurology Henry Ford HospitalDetroitMIUSA Department of Physics Oakland UniversityRochesterMIUSA Department of Pathology Henry Ford HospitalDetroitMIUSA Division of Pharmacology Department of NeuroscienceReproductive and Dentistry SciencesSchool of MedicineUniversity of Naples“Federico Ⅱ”NaplesItaly

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional *** previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression *** EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a *** male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or *** array of behavior assays was used to measure neurological *** with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological *** vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal *** analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct *** of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of *** data provide evidence that 27a-sEVs have

关键词： axonal remodeling cerebral endothelial cells exosomes miR-27a mitochondria Semaphorin 6A small extracellular vesicles stroke

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

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Neural Regeneration Research 2025年第7期20卷 1981-1988页

作者： Shan Ping Yu Emily Choi michael QJiang Ling Wei Department of Anesthesiology Emory University School of MedicineAtlantaGAUSA Center for Visual and Neurocognitive Rehabilitation Atlanta Veterans Affairs Medical CenterDecaturGAUSA

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same *** comorbidity of the two neurological disorders represents a grave health threat to older *** review presents a brief background of the development of novel concepts and their clinical *** activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal *** ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic *** Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute ***,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death *** on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic *** N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic *** stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time *** is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related

关键词： Ca^(2+)hypothesis cognitive deficits hyperactivity late-onset Alzheimer's disease neurodegeneration N-methyl-D-aspartate receptors N-methyl-D-aspartate receptor subunits pathogenesis preventive treatment

Deepening Collaboration China and Africa need to further align development strategies to realise the immense potential of economic cooperation

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ChinAfrica 2025年第1期17卷 24-26页

作者： EHIZUELEN michael MITCHELL OMORUYI Centre for Nigerian Studies Institute of African StudiesZhejiang Normal University

Humming factories,bustling ports,and shuttling merchan.s highlight the vibrancy of China-Africa economic and trade *** the years,this partnership has grown significantly,optimising trade structures and fostering mutual *** deepening collaboration is evident in China’s role as Africa’s largest bilateral trading partner for 15 consecutive *** the first seven months of 2024,trade between China and African countries reached$167 billion,reflecting a 5.5-percent increase compared to the same period in *** to the International Monetary Fund,approximately 20 percent of Africa’s exports now go to China,while 16 percent of its imports originate there.

关键词： trading deepening Africa

Scalable Ir-Doped NiFe₂O₄/TiO₂ Heterojunction Anode for Decentralized Saline Wastewater Treatment and H₂ Production

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NANO-MICRO LETTERS 2025年第1期17卷 1-18页

作者： Hong, Sukhwa Kim, Jiseon Park, Jaebeom Im, Sunmi Hoffmann, michael R. Cho, Kangwoo Pohang Univ Sci & Technol POSTECH Div Environm Sci & Engn Pohang 790784 South Korea CALTECH Linde Labs Pasadena CA 91125 USA Yonsei Univ Int Campus Inst Convergence Res & Educ Adv Technol I CREATE Incheon 21983 South Korea

Wastewater electrolysis cells (WECs) for decentralized wastewater treatment/reuse coupled with H-2 production can reduce the carbon footprint associated with transportation of water, waste, and energy carrier. This study reports Ir-doped NiFe2O4 (NFI, similar to 5 at% Ir) spinel layer with TiO2 overlayer (NFI/TiO2), as a scalable heterojunction anode for direct electrolysis of wastewater with circumneutral pH in a single-compartment cell. In dilute (0.1 M) NaCl solutions, the NFI/TiO2 marks superior activity and selectivity for chlorine evolution reaction, outperforming the benchmark IrO2. Robust operation in near-neutral pH was confirmed. Electroanalyses including operando X-ray absorption spectroscopy unveiled crucial roles of TiO2 which serves both as the primary site for Cl- chemisorption and a protective layer for NFI as an ohmic contact. Galvanostatic electrolysis of NH4+-laden synthetic wastewater demonstrated that NFI/TiO2 not only achieves quasi-stoichiometric NH4+-to-N-2 conversion, but also enhances H-2 generation efficiency with minimal competing reactions such as reduction of dissolved oxygen and reactive chlorine. The scaled-up WEC with NFI/TiO2 was demonstrated for electrolysis of toilet wastewater.

关键词： Wastewater electrolysis cell Ir-doped NiFe2O4 Reactive chlorine species Decentralized H-2 production On-site wastewater treatment

Mortality rate after total knee arthroplasty or total hip arthroplasty in patients with a history of liver transplant

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World Journal of Orthopedics 2024年第4期15卷 310-311页

作者： E Carlos Rodriguez-merchan Department of Orthopedic Surgery La Paz University Hospital-IdiPazMadrid 28046Spain

In this editorial I comment on the article by Ahmed et al published in a recent issue of the World J Orthop 2023;14:*** is well known that patients who have undergone a liver transplant(LT)may need to have a total hip arthroplasty(THA)or total knee arthroplasty(TKA)*** et al stated that the mortality rate in these patients was similar to the one of the general ***,there are three articles previously published that found higher mortality in LT patients who experienced THA/TKA than in the general population(individuals without LT).Therefore,in this Editorial I would like to point out that there is controversy in the literature regarding whether LT patients undergoing THA/TKA have higher mortality than the general ***,future research should attempt to resolve this controversy.

关键词： Liver transplant Total knee arthroplasty Total hip arthroplasty Results Mortality

A spotlight on dosage and subject selection for effective neuroprotection: exploring the central role of mitochondria

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Neural Regeneration Research 2025年第4期20卷 1081-1082页

作者： John Mitrofanis Jonathan Stone michael R.Hamblin Pierre Magistretti Alim-Louis Benabid Glen Jeffery Fonds Clinatec UniversitéGrenoble AlpesGrenobleFrance School of Medical Science University of SydneySydneyAustralia Faculty of Health Sciences University of JohannesburgJohannesburgSouth Africa King Abdullah University of Science and Technology ThuwalSaudi Arabia Institute of Ophthalmology University College LondonLondonUK

Neurons are notoriously vulnerable cell *** the slightest change in their internal and/or external environments will cause much distress and dysfunction,leading often to their death.A range of pathological conditions,including stroke,head trauma,and neurodegenerative disease,can generate stress in neurons,affecting their survival and proper *** most neural pathologies,mitochondria become dysfunctional and this plays a pivotal role in the process of cell *** challenge over the last few decades has been to develop effective interventions that improve neuronal homeostasis under pathological *** interventions,often referred to as disease-modifying or neuroprotective,have,however,proved frustratingly elusive,at both preclinical and,in particular,clinical *** this perspective,we highlight two factors that we feel are key to the development of effective neuroprotective *** are:firstly,the choice of dose of intervention and method of application,and secondly,the selection of subjects,whether they be patients or the animal model.

关键词： protective dosage distress

Effect of intensity and duration of anthropic noises on European mink locomotor activity and fecal cortisol metabolite levels

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Current Zoology 2022年第6期68卷 688-699页

作者： Lorena ORTIZ-JIMENEZ Carlos IGLESIAS-merchan.Alba Itzel MARTıNEZ-SALAZAR Isabel BARJA Department of Biology Zoology UnitUniversidad Autonoma de MadridMadrid28049Spain Department of Forest and Environmental Engineering and Management Universidad Politecnica de MadridMadridSpain Geographic Information Systems Laboratory Institute of BiologyUniversidad Nacional Autonoma de MexicoMexico CityMexico Biodiversity and Global Change Research Centre(CIBC-UAM) Universidad Autonoma de MadridMadridSpain

Human activities involving noise emission can affect wild *** mink was exposed to road noise and human voice playbacks to analyze how sound intensity level and duration of both noises altered the time that individuals were active and if their fecal cortisol metabolite(FCM)levels varied.A Hierarchical Analysis Cluster was performed to establish 2 mink groups with respect to both noise source type:short duration/low intensity(SL)and long duration/high intensity(LH).We performed general linear mixed models to evaluate the variation in locomotor activity duration(s)and FCM(nanogram per gram)levels,*** results showed both road noise and human voices decreased locomotor activity duration in SL more sharply compared with LH,and human voices were the triggers that induced the most pronounced response to both exposure ***(ng/g)levels increased in SL compared with LH during road noise while the opposite happened during human *** based on sex and age of individuals were *** conclusion,noise characteristics given by the sound type determined the variations in locomotor activity duration while noise exposure level determined the variations in FCM(ng/g)*** should be paid to noisy activities(e.g.,recreational activities for visitors in protected natural areas)and loud groups of people to conserve wildlife,especially noise sensitive species.

关键词： anthropic disturbances European mink fecal cortisol metabolites noise exposure locomotor activity behavioral response