Zoeb Jiwaji’s research while affiliated with University of Edinburgh and other places

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Publications (31)


Role of glia in delirium: proposed mechanisms and translational implications
  • Literature Review
  • Full-text available

October 2024

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21 Reads

Molecular Psychiatry

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Moritz Steinruecke

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Delirium is a common acute onset neurological syndrome characterised by transient fluctuations in cognition. It affects over 20% of medical inpatients and 50% of those critically ill. Delirium is associated with morbidity and mortality, causes distress to patients and carers, and has significant socioeconomic costs in ageing populations. Despite its clinical significance, the pathophysiology of delirium is understudied, and many underlying cellular mechanisms remain unknown. There are currently no effective pharmacological treatments which directly target underlying disease processes. Although many studies focus on neuronal dysfunction in delirium, glial cells, primarily astrocytes, microglia, and oligodendrocytes, and their associated systems, are increasingly implicated in delirium pathophysiology. In this review, we discuss current evidence which implicates glial cells in delirium, including biomarker studies, post-mortem tissue analyses and pre-clinical models. In particular, we focus on how astrocyte pathology, including aberrant brain energy metabolism and glymphatic dysfunction, reactive microglia, blood-brain barrier impairment, and white matter changes may contribute to the pathogenesis of delirium. We also outline limitations in this body of work and the unique challenges faced in identifying causative mechanisms in delirium. Finally, we discuss how established neuroimaging and single-cell techniques may provide further mechanistic insight at pre-clinical and clinical levels.

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FIGURE 1 Consequences of anesthesia on cortical transcription. (A) RNAseq used to determine cortical gene expression changes in mice exposed to 6 h isoflurane anesthesia. Genes significantly induced (red) and repressed (blue) are highlighted (expression cut-off > 1 FPKM, > 1.3 FC up or down, p values adjusted for multiple testing by the Benjamini-Hochberg procedure to give a false discovery rate of 5% (p_adj < 0.05) here and in all RNA-seq analyses; n = 5 animals per condition). (B) Ontological analysis of genes induced and repressed by anesthesia. Top ten most significantly enriched pathways are shown, with pathways with less than four significant genes or not relevant to tissue type omitted. (C) Fold change expression of immediate early and activity-regulated neuroprotective genes in mice undergoing 6 h isoflurane anesthesia v controls (Mean ± SEM fold change anesthesia v control, N = 5 animals per condition, *p_adj < 0.05, overall p-value < 0.001, 1-way ANOVA, all gene expression data shown here and elsewhere, unless otherwise stated, determined using RNA-sequencing).
FIGURE 2 Visual sensory deprivation and light-re-exposure determines activity-mediated CNS gene expression. (A) Visual cortex innervation from the retina allows manipulation of neuronal activity by exposure to conditions of light v darkness. (B) Schematic of experimental protocol. Mice were kept in normal light conditions, total darkness for 7 days, or total darkness for 6 days followed by 24 h of light-re-exposure. (C) Fold change immediate early gene expression in mice exposed to normal light conditions, 7 days of darkness or 6 days of darkness followed by 24 h light re-exposure v mean expression in mice kept in darkness (mean ± SEM, ***p-value < 0.001, 1-way ANOVA, N = 4 mice per condition here and in all experiments involving visual sensory deprivation and light-stimulation). (D) RNAseq analysis reveals the consequences of visual sensory deprivation on visual cortex gene expression. Genes significantly induced by normal light conditions v darkness (red) and repressed (blue) are highlighted (expression cut-off > 1 FPKM, FC up or down > 1.3, p_adj < 0.05). (E) 24 h light re-exposure following sustained darkness alters CNS gene expression. Genes significantly induced or repressed by 24 h light re-exposure v darkness (red) and repressed (blue) are highlighted (expression cut-off > 1 FPKM, FC up or down > 1.3, p_adj < 0.05). (F) Gene expression changes after 24 h light re-exposure v darkness in mice correlated with changes identified in mice kept in normal light conditions v darkness. Significantly altered genes in either paradigm are plotted to show log2 fold change expression in normal light v darkness and 24 h light-exposure v darkness (R2 and p-value from Pearson correlation).
FIGURE 7 (A) Anesthesia alters astrocyte gene expression and upregulates genes associated with both acute and chronic reactive states. Genes significantly induced (red) and suppressed (blue) are highlighted (expression cut-off 1 FPKM, FC > 1.3, p_adj < 0.05) (N = 4 animals per condition). (B) Ontological analysis of astrocyte genes induced and repressed by anesthesia. Top ten most significantly enriched pathways are shown, with pathways with less than 4 significant genes or not relevant to tissue type omitted. (C) Anesthesia overall upregulates pan-reactive astrocyte genes enhanced by both acute LPS and middle cerebral artery occlusion (MCAO). Gene lists derived from Zamanian et al. (2012), re-derived as described in Jiwaji and Hardingham (2022). Fold change astrocyte genes, anesthesia v control (expression cut-off > 1 FPKM, ratio paired 2-tailed t-test). (D) Anesthesia overall upregulates reactive astrocyte genes found to be commonly upregulated in end-stage amyloidopathy (APP/PS1 model) and end-stage tauopathy (MAPT-P301S model). Gene-list from Jiwaji and Hardingham (2022). Fold change astrocyte genes, anesthesia v control (expression cut-off > 1 FPKM, ratio paired 2-tailed t-test).
FIGURE 8 Consequences of visual sensory deprivation and light stimulation on astrocyte gene expression, and comparison with astrocyte genes changed by alternative stimulation paradigms and by ageing and disease. (A) TRAPseq identifies astrocyte genes altered by altered visual sensory experience. Genes significantly induced (red) and repressed (blue) are highlighted (expression cut-off > 1 FPKM, FC > 1.3, p_adj < 0.05) for normal light conditions v darkness (left) and with 24 h light-exposure (right). (B) Astrocyte genes upregulated by light re exposure overlap with astrocyte genes significantly enhanced by neuronal activity in vitro (gene-set from Hasel et al., 2017). Fold change light re-exposure v continuous darkness (expression cut-off > 1 FPKM, ratio paired 2-tailed t-test). (C) (left). Activity-dependent astrocyte genes upregulated by visual sensory stimulation (Normal light conditions v continuous darkness, expression cut-off > 1 FPKM, FC > 2, p_adj < 0.05) are significantly enriched in sets of astrocyte genes upregulated after 4 h light exposure in single-cell analysis of visual cortex; drug-induced seizures; and in mice experiencing sleep-deprivation v sleep. (*p-value < 0.05, Fisher's exact test). (C) (right). Activity-dependent astrocyte genes are enriched in sets of astrocyte genes reduced by ageing and in a mouse model of tauopathy. (*p-value < 0.05, Fisher's exact test).
General anesthesia alters CNS and astrocyte expression of activity-dependent and activity-independent genes

August 2023

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99 Reads

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1 Citation

Frontiers in Network Physiology

General anesthesia represents a common clinical intervention and yet can result in long-term adverse CNS effects particularly in the elderly or dementia patients. Suppression of cortical activity is a key feature of the anesthetic-induced unconscious state, with activity being a well-described regulator of pathways important for brain health. However, the extent to which the effects of anesthesia go beyond simple suppression of neuronal activity is incompletely understood. We found that general anesthesia lowered cortical expression of genes induced by physiological activity in vivo , and recapitulated additional patterns of gene regulation induced by total blockade of firing activity in vitro , including repression of neuroprotective genes and induction of pro-apoptotic genes. However, the influence of anesthesia extended beyond that which could be accounted for by activity modulation, including the induction of non activity-regulated genes associated with inflammation and cell death. We next focused on astrocytes, important integrators of both neuronal activity and inflammatory signaling. General anesthesia triggered gene expression changes consistent with astrocytes being in a low-activity environment, but additionally caused induction of a reactive profile, with transcriptional changes enriched in those triggered by stroke, neuroinflammation, and Aß/tau pathology. Thus, while the effects of general anesthesia on cortical gene expression are consistent with the strong repression of brain activity, further deleterious effects are apparent including a reactive astrocyte profile.


The consequences of neurodegenerative disease on neuron-astrocyte metabolic and redox interactions

August 2023

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28 Reads

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7 Citations

Neurobiology of Disease

Brain metabolic pathways relating to bioenergetic and redox homeostasis are closely linked, and deficits in these pathways are thought to occur in many neurodegenerative diseases. Astrocytes play important roles in both processes, and growing evidence suggests that neuron-astrocyte inter-cellular signalling ensures brain bioenergetic and redox homeostasis in health. Moreover, alterations to this crosstalk have been observed in the context of neurodegenerative pathology. In this review, we summarise the current understanding of how neuron-astrocyte interactions influence brain metabolism and antioxidant functions in health as well as during neurodegeneration. It is apparent that deleterious and adaptive protective responses alter brain metabolism in disease, and that knowledge of both may illuminate targets for future therapeutic interventions.


Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

June 2023

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472 Reads

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48 Citations

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.


Astrocyte-Oligodendrocyte interaction regulates central nervous system regeneration

October 2022

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66 Reads

Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells, astrocytes and mature myelin-forming oligodendrocytes, is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.


Good, bad, and neglectful: Astrocyte changes in neurodegenerative disease

February 2022

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38 Reads

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29 Citations

Free Radical Biology and Medicine

Astrocytes play key roles in CNS development as well as well as neuro-supportive roles in the mature brain including ionic, bioenergetic and redox homeostasis. Astrocytes undergo rapid changes following acute CNS insults such as stroke or traumatic brain injury, but are also profoundly altered in chronic neurodegenerative conditions such as Alzheimer's disease. While disease-altered astrocytes are often referred to as reactive, this does not represent a single cellular state or group of states, but a shift in astrocyte properties that is determined by the type of insult as well as spatio-temporal factors. Such changes can accelerate disease progression due to astrocytes neglecting their normal homeostatic neuro-supportive roles, as well as by gaining active neuro-toxic properties. However, other aspects of astrocytic responses to chronic disease can include the induction of adaptive-protective pathways. This is particularly the case when considering antioxidant defences, which can be up-regulated in many cell types, including astrocytes, in response to stresses, sometimes in concert with the activation of detoxification and proteostasis pathways. Protective responses, whilst potentially serving to mitigate neuronal dysfunction, may ultimately fail due to being insufficiently strong, or be offset by other deleterious changes to astrocytes occurring in parallel. Nevertheless, a greater understanding of early adaptive-protective responses of astrocytes to neurodegenerative disease pathology may point to ways in which these responses may be harnessed for therapeutic effect.


Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

January 2022

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332 Reads

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141 Citations

Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPT P301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.





Citations (7)


... Recently, an analysis of the proteome and metabolite secretome of astrocytes expressing hSOD1G93A showed alterations in GSH metabolism and signaling that were negatively regulated, while proteolytic processes were positively regulated [52]. In summary, astrocytes express and release antioxidants as part of their function in regulating redox balance by removing ROS to prevent oxidative damage to neurons [53]. ...

Reference:

Astrocytes, SOD1 and Amyotrophic Lateral Sclerosis: Mechanisms and Implications in Neurodegeneration
The consequences of neurodegenerative disease on neuron-astrocyte metabolic and redox interactions
  • Citing Article
  • August 2023

Neurobiology of Disease

... In WM, ApoE is lipidated to meet the lipid demands of oligodendrocytes, including cholesterol, phospholipids, sphingolipids, and glucosylceramides, which are essential for assembling and maintaining the multilayered membrane of the myelin sheath. These lipids act through lipidation, which occurs either within oligodendrocytes or via transport from astrocytes [18,23,24]. During aging, oligodendrocytes become less capable of synthesizing fatty acids (FAs) and lipids, leading to an increase in lipid transport from astrocytes to maintain myelin integrity, which are more vulnerable during pathological conditions [23,25,26]. ...

Astrocyte-oligodendrocyte interaction regulates central nervous system regeneration

... GFAP (a marker of astrocyte activation) was increased in our study at 6 weeks postpartum in dams as it was in their study at 8 weeks postpartum. Reactive astrocytes, associated with an increased GFAP expression and inflammatory cytokine production, can be present in HTN, and other CVDs, such as stroke and dementia (58,66). Astrocytes can produce proinflammatory cytokines, such IL-6 and TNF-α, as it does in HTN, hyperglycemia, and neurodegenerative disease states (58,67). ...

Good, bad, and neglectful: Astrocyte changes in neurodegenerative disease
  • Citing Article
  • February 2022

Free Radical Biology and Medicine

... Astrocytes are a diverse type of glial cells with remarkable plasticity that play a crucial role in maintaining the overall health and function of the central nervous system (CNS) (Allen and Eroglu, 2017;Ben Haim and Rowitch, 2017). In AD, astrocytes respond both functionally and morphologically to the neuropathologic markers of the disease, such as the clearance of excess neurotransmitters and toxic beta amyloid (Aβ) and tau protein forms of toxins (Jiwaji et al., 2022). Asterocyte dysfunction significantly influences the severity and developmental trajectory of AD (Tcw et al., 2022). ...

Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

... On DIV ~2, one-half of the medium was replaced with a growth medium containing the anti-mitotic cytosine arabinoside (Sigma-Aldrich) which restricts astrocytes and microglia to <0.01% (Hasel et al., 2018). Thereafter, the growth medium was replaced every other day. ...

Author Correction: Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism

... One potential mechanism for the regulation of Lcn2 expression during neuronal plasticity could be the cAMP-PKA-CREB pathway that is activated by the cLTP protocol used in our experiments. This pathway has been previously implicated in activity-dependent gene expression in astrocytes [66], and elevated astrocytic cAMP levels in vivo have been shown to trigger synaptic plasticity and influence memory formation [67]. ...

Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism

... The blockade of CREB phosphorylation by CCL2 could also contribute to this. In fact, CREB has shown to modulate lactate production in cultured astrocytes [44]. Also, the reduced release of lactate may indicate that the ATP obtained from glycogenolysis is being used by astrocytes for other purposes such as the refill of their endoplasmic reticulum stores of Ca 2+ through sarco/endoplasmic reticulum Ca 2 -ATPase (SERCA) pumps [45], or to increased mitochondrial oxidative metabolism of pyruvate formed through glycolytic pathway. ...

The role of neuronal activity in regulating metabolism in mouse and human astrocytes
  • Citing Article
  • February 2017

The Lancet