Alexei Verkhratsky

The University of Manchester · Faculty of Life Sciences

Astroglial perisynaptic sheath covers the majority of synapses in the central nervous system. This glial coverage evolved as a part of the synaptic structure in which elements directly responsible for neurotransmission (exocytotic machinery and appropriate receptors) concentrate in neuronal membranes, whereas multiple molecules imperative for homeo...

Neuroglia are represented by several population of cells heterogeneous in structure and function that provide for the homeostasis of the brain and the spinal cord. Neuroglial cells are also central for neuroprotection and defence of the central nervous system against exo- and endogenous insults. At the early stages of neurodegenerative diseases inc...

The entorhinal-hippocampal circuit is severely affected in Alzheimer's disease (AD). Here, we demonstrate that amyloid-β (Aβ) differentially affects primary cultured astrocytes derived from the entorhinal cortex (EC) and from the hippocampus from non-transgenic controls and 3xTg-AD transgenic mice. Exposure to 100 nM of Aβ resulted in increased exp...

The peripheral nervous system (PNS) consists of the nerves and ganglia outside of the brain and spinal cord. There are four major types of glia in the PNS. They are myelinating and non-myelinating Schwann cells, satellite glial cells (SGCs), enteric glial cells (EGCs), and olfactory ensheathing cells (OECs). Schwann cells support regeneration and s...

Astroglial excitability is largely mediated by fluctuations in intracellular ion concentrations. In addition to generally acknowledged Ca²⁺ excitability of astroglia, recent studies have demonstrated that neuronal activity triggers transient increases in the cytosolic Na⁺ concentration ([Na⁺](i)) in perisynaptic astrocytes. These [Na⁺](i) transient...

Cerebral small vessel disease (CSVD) leads to an extensive white matter damage associated with cognitive decline, yet the underlying damaging mechanisms remain incompletely understood. Here we established a positive correlation between plasma levels of serine proteinase elastase ELANE and periventricular white matter hyperintensity (PV-WMH) in a co...

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and a...

Mechanisms controlling the movement of the cerebrospinal fluid (CSF) toward peripheral nerves are poorly characterized. We found that, in addition to the foramina Magendie and Luschka for CSF flow toward the subarachnoid space and glymphatic system, CSF outflow could also occur along periaxonal spaces (termed “PAS pathway”) from the spinal cord to...

Astrocyte atrophy is the main histopathological hallmark of major depressive disorder (MDD) in humans and in animal models of depression. Here we demonstrated that manipulating with ezrin expression specifically in astrocytes significantly increases the resilience of mice to chronic unpredictable mild stress (CUMS). Overexpression of ezrin in astro...

Intracellular Ca2+ signalling represents the substrate of microglial excitability. Spatially and temporally organised changes in the free cytoplasmic Ca2+ concentration ([Ca2+]i) are generated in response to physiological and pathological stimuli. Parameters of these intracellular Ca2+ signals are defined by Ca2+ signalling toolkits that may change...

Microglia, which are the resident innate immune cells of the central nervous system (CNS), have emerged as critical for maintaining health by not only ensuring proper development, activity, and plasticity of neurones and glial cells but also maintaining and restoring homeostasis when faced with various challenges across the lifespan. This chapter i...

Microglial cells are the most receptive cells in the central nervous system (CNS), expressing several classes of receptors reflecting their immune heritage and newly acquired neural specialisation. Microglia possess, depending on the particular context, receptors to neurotransmitters and neuromodulators as well as immunocompetent receptors. This ri...

Neurodegenerative diseases are manifested by a progressive death of neural cells, resulting in the deterioration of central nervous system (CNS) functions, ultimately leading to specific behavioural and cognitive symptoms associated with affected brain regions. Several neurodegenerative disorders are caused by genetic variants or mutations, althoug...

There is no safe level of air pollution for human health. Traffic-related particulate matter (PM2.5) is a major in-utero toxin, mechanisms of action of which are not fully understood. BALB/c dams were exposed to an Australian level of traffic PM2.5 (5 µg/mouse/day, intranasal, 6 weeks before mating, during gestation and lactation). Male offspring h...

Alzheimer's disease (AD) is the major cause of senile dementia without effective therapeutic strategies. The fundamental role of microglia in AD pathology, particularly in the early stages, is well acknowledged, although cell-specific therapeutic targets were not identified. Here we show that microglial connexin 43 (Cx43) hemichannels controls micr...

Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer’s disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory...

Hepatic encephalopathy (HE) following acute liver failure (ALF) is a primary toxic astrocytopathy, although in-depth characterisation of underlying pathogenesis is far from complete. Among the multitude of astrocyte-specific proteins guiding brain functionality, plasmalemma-cytoskeletal linker ezrin, actin-binding protein profilin-1, and water chan...

The concept of cognitive reserve was born to account for the disjunction between the objective extent of brain damage in pathology and its clinical and intellectual outcome. The cognitive reserve comprises structural (brain reserve) and functional (brain maintenance, resilience, compensation) aspects of the nervous tissue reflecting exposome-driven...

Astrocytes belong to an extended class of astroglia, a class of neural cells of ectodermal, neuroepithelial origin that sustain homeostasis and provide for defense of the brain and the spinal cord. Astroglial cells support homeostasis of the central nervous system at all levels of organization from molecular to organ-wide. Astrocytes cannot generat...

The way the central nervous system (CNS) responds to diverse stimuli is contingent upon the specific brain state of the individual, including sleep and wakefulness. Despite the wealth of readout parameters and data delineating the brain states, the primary mechanisms are yet to be identified. Here we highlight the role of astrocytes, with a specifi...

The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer’s disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of...

Aim Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in...

Neuropathic pain is a chronic debilitating condition caused by nerve injury or a variety of diseases. At the core of neuropathic pain lies the aberrant neuronal excitability in the peripheral and/or central nervous system (PNS and CNS). Enhanced connexin expression and abnormal activation of connexin-assembled gap junctional channels are prominent...

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (AD...

Bioelectronic Medicine stands as an emerging field that rapidly evolves and offers distinctive clinical benefits, alongside unique challenges. It consists of the modulation of the nervous system by precise delivery of electrical current for the treatment of clinical conditions, such as post-stroke movement recovery or drug-resistant disorders. The...

Modern neuroscience began from all reaching and fierce conflict between “neuronismo and reticulismo” – between neuronal and reticular theories of the organization of the nervous system; the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal (the proponent of the neuronal doctrine) and Camillo Golgi (who advocated the...

The pandemic of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) instigated the most serious global health crisis. Clinical presentation of COVID-19 frequently includes severe neurological and neuropsychiatric symptoms. However, it is presently unknown whether and to which extent pathologica...

Background Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte–microglia interaction, which both contribute to evolution of NMOSD lesions. Main body Through transcriptomic and flow cytometry analyses, we found that Bruton’s t...

We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred aroun...

How aging affects cells of the human brain active milieu remains largely unknown. Here, we analyze astrocytes and neurons in the neocortical tissue of younger (22–50 years) and older (51–72 years) adults. Aging decreases the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The protein-to-lipid ratio decreases in astrocytes...

Astrocytes safeguard the homeostasis of the central nervous system 1,2 . Despite their prominent morphological plasticity under conditions that challenge the brain’s adaptive capacity 3–5 , the classification of astrocytes, and relating their molecular make-up to spatially devolved neuronal operations that specify behavior or metabolism, remained m...

Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, the molecular signature of foetal astrocyte evolution in primates is unknown. Here, to address this question, we use human, chimpanzee, and macaque induced pluripotent stem cell-derived foetal astrocytes (i...

Objective: Sophorae Flavescentis Radix (Kuh-seng, SFR), a Traditional Chinese Medicine (TCM), is widely used alone or within a TCM formula to treat pruritus, especially histamine-independent intractable itching. In the previous study, potential antipruritic active components of the SFR were screened based on cell membrane immobilized chromatograph...

Inflammatory pain, sustained by a complex network of inflammatory mediators, is a severe and persistent illness affecting many of the general population. We explore possible anti-inflammatory pathways of Polyphyllin VI (PPVI) based on our prior study, which showed that PPVI reduces inflammation in mice to reduce pain. Network pharmacology and RNA-S...

Background and objective: Itch, an unpleasant sensation prompting the urge to scratch, and pain, aimed at detecting potential harm through acute withdrawal or protective behaviors, are increasingly recognized as interconnected phenomena. The co-occurrence of itch and pain symptoms in various diseases impairs therapeutic efficacy and the quality of...

Mechanisms controlling movement of the CSF through the central canal towards the peripheral nerves are poorly characterized. We found that fluorescent dyes injected into cisterna magna are carried with cerebrospinal fluid (CSF) through the central canal and peripheral nerves to the peripheral organs such as liver, and pancreas. We also found close...

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia...

Ke y w ords: scientific errors; correction of errors; fraud; irreproducibility; wrong methodology The famous phrase "Errar e human um est, sed in errare perse-v erar e dia bolicum" ("To err is human, but to persist in error is diabolical"), which is attributed to the Roman philosopher and orator Lucius Annaeus Seneca (∼4 bce to 65 ce), is as r elev...

The immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human M...

The pandemic of Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) instigated the most serious global health crisis. Clinical presentation of COVID-19 frequently includes severe neurological and neuropsychiatric symptoms. However, it is presently unknown whether and to which extent pathologica...

Neuronal morphogenesis relies on intercellular signaling. Astrocytes release metabolites, trophic, and guidance factors to promote neuronal differentiation. In contrast, the mechanisms by which astrocytes could limit and stabilize neuronal connectivity remain less explored. Here, we show cortical astrocytes to express and release S100A6, a Ca2+-bin...

The purinoceptor P2X7R is a promising therapeutic target for tauopathies, including Alzheimer’s disease (AD). Pharmacological inhibition or genetic knockdown of P2X7R ameliorates cognitive deficits and reduces pathological tau burden in mice that model aspects of tauopathy, including mice expressing mutant human frontotemporal dementia (FTD)-causin...

Inflammatory pain, sustained by a complex network of inflammatory mediators, is a severe and persistent illness affecting a large proportion of the general population. Based on our earlier research showing that Polyphyllin VI (PPVI) alleviates pain by reducing inflammation in mice we proceed to identify potential anti-inflammatory mechanisms of PPV...

Astrocyte atrophy is the main histopathological hallmark of major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to chronic unpredictable mild stress (CUMS). Treatment of mice w...

Nervous system pathophysiology is poorly understood. This translates into limited therapeutic options for neurological diseases, ranging from neurodegenerative diseases to neuropsychiatric disorders. The deficits in our knowledge reflect the complexity of the human brain, which is certainly the most complex system that confronts the natural science...

Adult oligodendrocyte precursor cells (aOPCs), transformed from fetal OPCs, are idiosyncratic neuroglia of the central nervous system (CNS) that are distinct in many ways from other glial cells. OPCs have been classically studied in the context of their remyelinating capacity. Recent studies, however, revealed that aOPCs not only contribute to post...

Lia et al. [1] discovered the critical role of STIM1 ER Ca2+ sensor in the functional decline of astrocytes in the AD-like pathology in PS2APP mice. Profound downregulation of STIM1 expression in astrocytes in the disease results in the decreased ER Ca2+ content and severely impaired evoked as well as spontaneous astrocytic Ca2+ signalling. Aberran...

Ageing is associated with a morphological and functional decline of astrocytes with a prevalence of morphological atrophy and loss of function. In particular, ageing is manifested by the shrinkage of astrocytic processes: branches and leaflets, which decreases synaptic coverage. Astrocytic dystrophy affects multiple functions astrocytes play in the...

Locomotion triggers a coordinated response of both neurons and astrocytes in the brain. Here we performed calcium (Ca2+) imaging of these two cell types in the somatosensory cortex in head-fixed mice moving on the airlifted platform. Ca2+ activity in astrocytes significantly increased during locomotion from a low quiescence level. Ca2+ signals firs...

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiolo...

Textbook of neuroglia covering all aspects of glial physiology and pathophysiology.

Information transfer within neuronal circuits depends on the balance and recurrent activity of excitatory and inhibitory neurotransmission. Chloride (Cl⁻) is the major central nervous system (CNS) anion mediating inhibitory neurotransmission. Astrocytes are key homoeostatic glial cells populating the CNS, although the role of these cells in regulat...

Neuropathological mechanisms of manic syndrome or manic episodes in bipolar disorder remain poorly characterised, as the research progress is severely limited by the paucity of appropriate animal models. Here we developed a novel mania mice model by combining a series of chronic unpredictable rhythm disturbances (CURD), which include disruption of...

Adult neurogenesis is a striking example of neuroplasticity, which enables adaptive network remodelling in response to all forms of environmental stimulation in physiological and pathological contexts. Dysregulation or cessation of adult neurogenesis contributes to neuropathology negatively affecting brain functions and hampering regeneration of th...

Astrocytes contribute to the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we report the neuroanatomical and morphometric analysis of astrocytes in the entorhinal cortex (EC) of the aged wild type (WT) and triple transgenic (3xTg-AD) mouse model of AD. Using 3D confocal microscopy, we determined the surface ar...

Protein misfolding is prominent in early cellular pathology of Alzheimer's disease (AD), implicating pathophysiological significance of endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) and highlighting it as a target for drug development. Experimental data from animal AD models and observations on human specimens are, however,...

Astrocyte atrophy is the main histopathological hallmark of the major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to the chronic unpredictable mild stress (CUMS). Treatment o...

Astrocytes display a highly complex, spongiform morphology, with their fine terminal processes (leaflets) exercising dynamic degrees of synaptic coverage, from touching and surrounding the synapse to being retracted from the synaptic region. In this paper, a computational model is used to reveal the effect of the astrocyte-synapse spatial relations...

Astrocyte atrophy is the main histopathological hallmark of the major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to the chronic unpredictable mild stress (CUMS). Treatment o...

Objective: Inflammatory pain is one of the most common diseases in daily life and clinic. In this work, we analysed bioactive components of the traditional Chinese medicine Chonglou and studied mechanisms of their analgesic effects. Material and methods: Molecular docking technology and U373 cells overexpressing P2X3 receptors combined with the cel...

Nervous system is segregated from the body by the complex system of barriers. The CNS is protected by (i) the blood-brain and blood-spinal cord barrier between the intracerebral and intraspinal blood vessels and the brain parenchyma; (ii) the arachnoid blood-cerebrospinal fluid barrier; (iii) the blood-cerebrospinal barrier of circumventricular org...