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Alterations of protein homeostasis in Alzheimer's disease:beyond Procrustean bed of endoplasmic reticulum stress and unfolded protein response

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Neural Regeneration Research 2024年第8期19卷 1645-1646页

作者： Dmitry Lim alexei verkhratsky Department of Pharmaceutical Sciences Universitàdel Piemonte Orientale“Amedeo Avogadro”NovaraItaly Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Achucarro Center for Neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain&Department of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain Department of Stem Cell Biology State Research Institute Centre for Innovative MedicineVilniusLithuania Department of Forensic Analytical Toxicology School of Forensic MedicineChina Medical UniversityShenyangLiaoning ProvinceChina

Alzheimer’s disease(AD)is a major age-related form of dementia with a number of cases exponentially growing,causing enormous social and economic impact on individuals and society.Neuropathological hallmarks of AD,evident in postmortem AD brains,include a massive loss of the grey matter in the neocortex,extracellular deposition of amyloid-β(Aβ)in the form of senile plaques and cerebrovascular amyloid angiopathy,and intra-neuronal accumulation of neurofibrillary tangles,formed by hyper-phosphorylated tau protein.

关键词： Alzheimer homeostasis cortex

Astrocytes dynamically regulate the blood-brain barrier in the healthy brain

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Neural Regeneration Research 2024年第4期19卷 709-710页

作者： AgnėPociūtė Augustas Pivoriūnas alexei verkhratsky Department of Stem Cell Biology State Research Institute Centre for Innovative MedicineVilniusLithuania Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Achucarro Centre for Neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain Department of Forensic Analytical Toxicology School of Forensic MedicineChina Medical UniversityShenyangLiaoning ProvinceChina

The blood-brain barrier(BBB)(discovered and defined by Max Lewandowsky and Lina Stern,and not,as it is universally,and yet erroneously believed,by Paul Ehrlich(verkhratsky and Pivoriunas,2023))that separates the nervous system from the circulation is evolutionarily conserved from arthropods to man.The primeval BBB of the invertebrates and some early vertebrates was made solely by glial cells and secured(in invertebrates)by septate junctions.

关键词： Ehrlich barrier blood

Astrocyte chloride,excitatory-inhibitory balance and epilepsy

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Neural Regeneration Research 2024年第9期19卷 1887-1887页

作者： Verena Untiet Maiken Nedergaard alexei verkhratsky Division of Glial Disease and Therapeutics Center for Translational NeuromedicineUniversity of CopenhagenCopenhagenDenmark Division of Glial Disease and Therapeutics Center for Translational NeuromedicineDepartment of NeurosurgeryUniversity of Rochester Medical CenterRochesterNYUSA Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Achucarro Centre for Neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoSpain

Excitation and inhibition are at the core of brain function and malfunction.To sustain the activity of neuronal networks over time and space,glutamatergic excitation is balanced by GABAergic inhibition.The equipoise of excitation and inhibition,known as the excitation/inhibition(E/I)balance,is crucial for proper brain function.The E/I balance is highly dynamic and shifts across different brain states:wakefulness primarily augments excitatory activity,while sleep promotes a decrease in excitation and an increase in inhibition(Bridi et al.,2020).Neuronal activity during various brain states is primarily regulated by neurotransmitters(Schiemann et al.,2015),alongside non-synaptic mechanisms that operate on a slower timescale.The non-synaptic mechanisms are many,with the ionic composition of the extracellular space playing a significant role;altering extracellular ion concentrations affects sleep,arousal,electroencephalogram patterns,and behavioral states(Ding et al.,2016).

关键词： epilepsy excitatory excitation

Decline and fall of aging astrocytes:the human perspective

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Neural Regeneration Research 2025年第6期 1713-1714页

作者： alexei verkhratsky Alexey Semyanov Faculty of Biology Medicine and Health The University of Manchester Department of Neurosciences University of the Basque Country UPV/EHU and CIBERNED Department of Forensic Analytical Toxicology School of Forensic Medicine China Medical University Department of Stem Cell Biology State Research Institute Centre for Innovative Medicine International Collaborative Center on Big Science Plan for Purinergic Signalling Chengdu University of Traditional Chinese Medicine Department of Physiology Jiaxing University College of Medicine

“Last scene of all that ends this strange, eventful history, is second childishness and mere oblivion. I am sans teeth, sans eyes, sans taste, sans everything.”William Shakespeare‘As You Like It' Act 2, Sc. 7, l. 139Aging of the human brain is characterized by a progressive decline of its functional capacity; this decline however varies widely, and cognitive longevity differs substantially between individuals.

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Astrocytes in Post-traumatic Stress Disorder

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Neuroscience Bulletin 2022年第8期38卷 953-965页

作者： Baoman Li Dianjun Zhang alexei verkhratsky Department of Forensic Analytical Toxicology School of Forensic MedicineChina Medical UniversityShenyang 110122China Faculty of Biology Medicine and HealthThe University of ManchesterManchester M139PTUK Department of Stem Cell Biology State Research Institute Centre for Innovative Medicine01102 VilniusLithuania

Although posttraumatic stress disorder(PTSD)is on the rise,traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself.Traumatic experiences can be broadly classified into mental stress(MS)and traumatic brain injury(TBI),but the cellular mechanisms of MS-or TBI-induced PTSD remain unknown.Recent evidence has shown that the morphological remodeling of astrocytes accompanies and arguably contributes to fearful memories and stressrelated disorders.In this review,we summarize the roles of astrocytes in the pathogenesis of MS-PTSD and TBIPTSD.Astrocytes synthesize and secrete neurotrophic,proand anti-inflammatory factors and regulate the microenvironment of the nervous tissue through metabolic pathways,ionostatic control,and homeostatic clearance of neurotransmitters.Stress or trauma-associated impairment of these vital astrocytic functions contribute to the pathophysiological evolution of PTSD and may present therapeutic targets.

关键词： Astrocytes Traumatic brain injury Traumatic events Neurotrophic factors Serotonin

Glial decline and loss of homeostatic support rather than inflammation defines cognitive aging

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Neural Regeneration Research 2022年第3期17卷 565-566页

作者： alexei verkhratsky Natalia Lazareva Alexey Semyanov Faculty of Biology Medicine and HealthThe University of ManchesterManchesterUK Achucarro Center for Neuroscience IKERBASQUEBasque Foundation for ScienceBilbaoDepartment of NeurosciencesUniversity of the Basque Country UPV/EHU and CIBERNEDLeioaSpain Sechenov First Moscow State Medical University MoscowRussia Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of SciencesFaculty of BiologyMoscow State UniversityMoscowRussia

The preservation of cognitive longevity and arresting the pandemic of senile dementia engulfing the modern world is arguably the major challenge faced by biomedical research in the 21st century.Age is the leading risk factor for neurodegenerative diseases and vascular dementia,and yet there is a clear distinction between physiological and pathological brain aging.

关键词： inflammation senile aging

Glial calcium signaling in physiology and pathophysiology

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Acta Pharmacologica Sinica 2006年第7期27卷 773-780页

作者： alexei verkhratsky Faculty of Life Sciences the University of Manchester UK

Neuronal-glial circuits underlie integrative processes in the nervous system.Func-tion of glial syncytium is,to a very large extent,regulated by the intracellularcalcium signaling system.Glial calcium signals are triggered by activation ofmultiple receptors,expressed in glial membrane,which regulate both Ca2+entryand Ca2+release from the endoplasmic reticulum.The endoplasmic reticulum alsoendows glial cells with intracellular excitable media,which is able to produce andmaintain long-ranging signaling in a form of propagating Ca2+waves.In patho-logical conditions,calcium signals regulate glial response to injury,which mighthave both protective and detrimental effects on the nervous tissue.

关键词： calcium signaling neuronal-glial interactions brain ischemia Alzheimer’s disease epilepsy spreading depression

Store-operated calcium entry in neuroglia

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Neuroscience Bulletin 2014年第1期30卷 125-133页

作者： alexei verkhratsky Vladimir Parpura Faculty of Life Sciences The University of Manchester Achucarro Center for Neuroscience IKERBASQUE Basque Foundation for Science 48011 Bilbao Spain and Department of Neurosciences University of the Basque Country UPV/EHU Department of Neurobiology Center for Glial Biology in Medicine Atomic Force Microscopy & Nanotechnology aboratories Civitan International Research Center Evelyn F. McKnight Brain Institute University of Alabama Department of Biotechnology University or Rijeka

Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca^2＋ signals that define the ＂Ca^2＋ excitability＂ of glia. In mammalian glial cells the major source of Ca^2＋ for this excitability is the lumen of the endoplasmic reticulum （ER）, which is ultimately （re）filled from the extracellular space. This occurs via store-operated Ca^2＋ entry （SOCE） which is supported by a specific signaling system connecting the ER with plasmalemmal Ca^2＋ entry. Here, emptying of the ER Ca^2＋ store is necessary and sufficient for the activation of SOCE, and without Ca^2＋ influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca^2＋ sensors, such as stromal interaction molecule, and possibly ER Ca^2＋ pumps （of the SERCA type）. There are at least two sets of plasmalemmal channels mediating SOCE, the Ca2＊-release activated channels, Orai, and transient receptor potential （TRP） channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca^2＋ signal observed following stimulation of metabotropic receptors on glial cells.

关键词： calcium signaling astrocyte oligodendrocyte microglia store-operated calcium entry TRP STIM Orai

Glial-neuronal Sensory Organs:Evolutionary Journey from Caenorhabditis elegans to Mammals

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Neuroscience Bulletin 2020年第5期36卷 561-564页

作者： Yong Tang Peter Illes alexei verkhratsky International Collaborative Centre on Big Science Plan for Purine Signalling Chengdu University of Traditional Chinese MedicineChengdu 610075China Acupuncture and Tuina School Chengdu University of TCMChengdu 610075China Key Laboratory of Sichuan Province for Acupuncture and Chronobiology Chengdu 610075China Rudolf-Boehm-Institut für Pharmakologie und Toxikologie Universitat LeipzigLeipzig 04107Germany Faculty of Biology Medicine and HealthThe University of ManchesterManchester MI39PTUK

Recently,a paper published in Science reported discovery of sensory peripheral glial cells[1].This paper demonstrated a rather unexpected property of non-myelinating Schwann cells(also known as Remak cells)dwelling in the subepidermal border of the skin[2].These glial cells and their interactions with nociceptive nerve terminals were characterized using a variety of genetic labelling tools,transmission electron microscopy,immunocytochemistry.

关键词： myelin border property