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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.w.lfe 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 w.th 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.w. focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unw.nding,”and“Tilting-Unw.nding,”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 w.s identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that w.s reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both w.ldtype and mutant Notch,being consistent w.th 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 w.ether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathw.ys 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 w.ng 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 w.ll characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members w.re initially discovered due to their interactions w.th other proteins. NECAB1 associates w.th synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NECAB2 interacts w.th predominantly striatal G-protein-coupled receptors, w.ile NECAB3 partners w.th 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 w.th 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 w.llcharacterized 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. How.ver, 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 betw.en the EF hands and the antibiotic biosynthesis monooxygenase domain. This review.summarizes w.at is know. 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 w.th 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 Zhongw. 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 grow.h of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic *** the present study,w. investigated w.ether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal grow.h and improve neurological outcomes after ischemic stroke w.en compared w.th treatment w.th non-engineered CEC-sEVs.27a-sEVs w.re isolated from the conditioned medium of healthy mouse CECs transfected w.th a lentiviral miR-27a expression *** EVs isolated from CECs transfected w.th a scramble vector(Scra-sEVs)w.re used as a *** male mice w.re subjected to permanent middle cerebral artery occlusion and then w.re randomly treated w.th 27a-sEVs or *** array of behavior assays w.s used to measure neurological *** w.th treatment of ischemic stroke w.th Scra-sEVs,treatment w.th 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,w.ile quantitative reverse transcription-polymerase chain reaction and w.stern Blot analysis show.d 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 pathw.y 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

Chemical cues from kingsnakes do not cause inducible defenses in house mice

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Current Zoology 2012年第6期58卷 797-804页

作者： w. w.llace STARKE Ⅲ michael H. FERKIN Department of Biological Sciences Ellington Hall University of Memphis Memphis TN 38152 USA

Abstract Many rodents exhibit inducible defenses w.en exposed to chemical cues from mammalian predators. These responses may include delays in sexual maturation, smaller adult body size and decreases in litter size and pup w.ight. w. exposed the hybrid juvenile offspring of field-caught and lab-descended house mice Mus musculus to the chemical cues of mouse-fed or chick-fed kingsnakes, Lampropeltis getula, for 20 days after w.aning, to examine the effects of ophidian predator cues on prey development. w. hypothesized that these cues w.uld elicit inducible defenses such as alteration of grow.h rates, and/or the timing of reproductive development in mice. Once mature, the reproductive effort of the mice might also be impacted by producing smaller litter sizes or lighter pups or not reproducing at all. w. found no effect of kingsnake cues on any of the measures. These findings support the hypothesis that inducible defenses may have evolved as a strategy to deal w.th specific predators.

关键词： Inducible defenses House mice Kingsnakes Chemical cues Grow.h and development

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 w.i 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 tw. 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 w.thin a few.hours and days know. 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 w.th much different time *** is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals w.o 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

The effects of cues from kingsnakes on the reproductive effort of house mice

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Current Zoology 2013年第1期59卷 135-141页

作者： w. w.llace STARKE III michael H. FERKIN Department of Biological Sciences University of Memphis Memphis TN 38152 USA

It is not clear if rodents express inducible defenses in response to reptilian predators such as snakes. w. tested the hypothesis that adult house mice Mus musculus decrease aspects of their reproductive effort upon 1 hour of exposure every 48 hours for a 25-day period to the fecal material and shed skins of a euryphagous ophidian predator, the kingsnake Lampropeltis getula, that had been fed mice. w. found no significant differences in the total number of offspring born, the number of pups per litter, and the mean w.ight of pups in litters born to male and female mice that w.re exposed to predator cues and those mice that w.re not exposed to such cues. The lack of an inducible response may be associated w.th the low.cost of an effective defense, or the lack of an effective defense against a generalist snake predator [Current Zoology 59 （1）： 135-141, 2013].

关键词： Inducible defenses Breeding suppression Lampropeltis getula Mus musculus Predator-prey interactions

A novel method for clustering cellular data to improve classification

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Neural Regeneration Research 2025年第9期20卷 2697-2705页

作者： Diek w.w.eeler Giorgio A.Ascoli Center for Neural Informatics Structures&PlasticityKrasnow Institute for Advanced Study Bioengineering Department Volgenau School of Engineering George Mason University FairfaxVAUSA

Many fields,such as neuroscience,are experiencing the vast prolife ration of cellular data,underscoring the need fo r organizing and interpreting large datasets.A popular approach partitions data into manageable subsets via hierarchical clustering,but objective methods to determine the appropriate classification granularity are *** recently introduced a technique to systematically identify w.en to stop subdividing clusters based on the fundamental principle that cells must differ more betw.en than w.thin *** w. present the corresponding protocol to classify cellular datasets by combining datadriven unsupervised hierarchical clustering w.th statistical *** general-purpose functions are applicable to any cellular dataset that can be organized as tw.-dimensional matrices of numerical values,including molecula r,physiological,and anatomical *** demonstrate the protocol using cellular data from the Janelia MouseLight project to chara cterize morphological aspects of neurons.

关键词： cellular data clustering dendrogram data classification Levene's one-tailed statistical test unsupervised hierarchical clustering