Publications by category
Journal articles
Piers TM, Cosker K, Mallach A, Johnson GT, Guerreiro R, Hardy J, Pocock JM (In Press). A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia.
Abstract:
A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia
AbstractLoss-of-function genetic variants oftriggering receptor expressed on myeloid cells 2 (TREM2)are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic function in human patient iPSC-derived-microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer’s disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
Abstract.
Mallach A, Gobom J, Arber C, Piers TM, Hardy J, Wray S, Zetterberg H, Pocock J (In Press). Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons.
Abstract:
Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons
AbstractMicroglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of the triggering receptor expressed myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins, and were less able to promote outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from TREM2 common variant iPS-Mg. Taken together these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47HhetTREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.Graphical Abstract
Abstract.
Cosker K, Mallach A, Limaye J, Piers TM, Staddon J, Neame SJ, Hardy J, Pocock JM (In Press). Microglial signalling pathway deficits associated with the R47H TREM2 variant linked to AD indicate inability to activate inflammasome.
Abstract:
Microglial signalling pathway deficits associated with the R47H TREM2 variant linked to AD indicate inability to activate inflammasome
AbstractThe R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.
Abstract.
Wei J, Arber C, Wray S, Hardy J, Piers TMM, Pocock JMM (2023). Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN- response pathway activation and senescence in differentiated microglia; an early life stress model.
GLIA,
71(4), 1036-1056.
Author URL.
Magusali N, Graham AC, Piers TM, Panichnantakul P, Yaman U, Shoai M, Reynolds RH, Botia JA, Brookes KJ, Guetta-Baranes T, et al (2021). A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the <i>OAS1</i> gene.
Brain,
144(12), 3727-3741.
Abstract:
A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene
Abstract
. Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known.
. Using genotyping from 1313 individuals with sporadic Alzheimer’s disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer’s disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer’s disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer’s disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells.
. Collectively, our data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.
Abstract.
Nazish I, Arber C, Piers TM, Warner TT, Hardy JA, Lewis PA, Pocock JM, Bandopadhyay R (2021). Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells. Neurochemistry International, 147, 105070-105070.
Mallach A, Gobom J, Arber C, Piers TM, Hardy J, Wray S, Zetterberg H, Pocock J (2021). Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons.
Cells,
10(11), 2866-2866.
Abstract:
Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47Hhet TREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.
Abstract.
Pocock JM, Piers TM (2018). Modelling microglial function with induced pluripotent stem cells: an update. Nature Reviews Neuroscience, 19(8), 445-452.
Yi JH, Kim DH, Piers TM, Kim SC, Whitcomb DJ, Regan P, Cho K (2018). Postsynaptic p47phox regulates long-term depression in the hippocampus.
Cell Discovery,
4(1).
Abstract:
Postsynaptic p47phox regulates long-term depression in the hippocampus
AbstractIt is well documented that reactive oxygen species (ROS) affects neurodegeneration in the brain. Several studies also implicate ROS in the regulation of synapse function and learning and memory processes, although the precise source of ROS generation within these contexts remains to be further explored. Here we show that postsynaptic superoxide generation through PKCζ-activated NADPH oxidase 2 (NOX2) is critical for long-term depression (LTD) of synaptic transmission in the CA1–Shaffer collateral synapse of the rat hippocampus. Specifically, PKCζ-dependent phosphorylation of p47phox at serine 316, a NOX2 regulatory subunit, is required for LTD but is not necessary for long-term potentiation (LTP). Our data suggest that postsynaptic p47phox phosphorylation at serine 316 is a key upstream determinant for LTD and synapse weakening.
Abstract.
Jebelli JD, Piers TM (2015). Amyloid-β oligomers unveil a novel primate model of sporadic Alzheimer's disease. Frontiers in Neuroscience, 9
Whitcomb DJ, Hogg EL, Regan P, Piers T, Narayan P, Whitehead G, Winters BL, Kim D-H, Kim E, St George-Hyslop P, et al (2015). Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus.
Scientific Reports,
5(1).
Abstract:
Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus
AbstractThe acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca2+-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
Abstract.
Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ (2015). Neuroprotection by safinamide in the 6‐hydroxydopamine model of <scp>P</scp>arkinson's disease.
Neuropathology and Applied Neurobiology,
42(5), 423-435.
Abstract:
Neuroprotection by safinamide in the 6‐hydroxydopamine model of Parkinson's disease
AimsCurrent therapies in Parkinson's disease mainly treat symptoms rather than provide effective neuroprotection. We examined the effects of safinamide (monoamine oxidase B and sodium channel blocker) on microglial activation and the degeneration of dopaminergic neurons in a rat model of PD
in vivo, and on microglia in vitro.MethodsRats received unilateral stereotaxic injection of 6‐hydroxydopamine into the medial forebrain bundle on day 0: the contralateral side served as control. Safinamide or vehicle was delivered from days 0 or 1, for 7 days, via sub‐cutaneous mini‐pumps.ResultsIn vehicle‐treated rats 6‐hydroxydopamine caused a significant increase in the number of activated MHC‐II+ microglia compared with the contralateral side, and only 50% of the dopaminergic neurons survived in the ipsilateral SNc. In contrast, rats treated daily with safinamide 50 and 150 mg/ml (on day 0 or 1) exhibited a significantly reduced number of activated microglia (55% reduction at 150 mg/ml) and a significant protection of dopaminergic neurons (80% of neurons survived) (P < 0.001) compared with vehicle‐treated controls. Rasagiline, a monoamine oxidase B inhibitor, and lamotrigine, a sodium channel blocking drug, also protected dopaminergic neurons, indicating that safinamide may act by either or both mechanisms. Safinamide also reduced the activation of microglial cells in response to lipopolysaccharide exposure in vitro.ConclusionSafinamide therapy suppresses microglial activation and protects dopaminergic neurons from degeneration in the 6‐hydroxydopamine model of PD, suggesting that the drug not only treats symptoms but also provides neuroprotection.
Abstract.
Jebelli J, Piers T, Pocock J (2015). Selective Depletion of Microglia from Cerebellar Granule Cell Cultures Using L-leucine Methyl Ester. Journal of Visualized Experiments(101).
Regan P, Piers T, Yi J-H, Kim D-H, Huh S, Park SJ, Ryu JH, Whitcomb DJ, Cho K (2015). Tau Phosphorylation at Serine 396 Residue is Required for Hippocampal LTD.
The Journal of Neuroscience,
35(12), 4804-4812.
Abstract:
Tau Phosphorylation at Serine 396 Residue is Required for Hippocampal LTD
Tau is required for the induction of long-term depression (LTD) of synaptic transmission in the hippocampus. Here we probe the role of tau in LTD, finding that an AMPA receptor internalization mechanism is impaired in tau KO mice, and that LTD causes specific phosphorylation at the serine 396 and 404 residues of tau. Surprisingly, we find that phosphorylation at serine 396, specifically, is critical for LTD but has no role in LTP. Finally, we show that tau KO mice exhibit deficits in spatial reversal learning. These findings underscore the physiological role for tau at the synapse and identify a behavioral correlate of its role in LTD.
Abstract.
Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, et al (2014). Microtubule-associated protein tau is essential for long-term depression in the hippocampus.
Philosophical Transactions of the Royal Society B: Biological Sciences,
369(1633), 20130144-20130144.
Abstract:
Microtubule-associated protein tau is essential for long-term depression in the hippocampus
. The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice
. in vivo
. and
. in vitro
. an effect that was replicated by RNAi knockdown of tau
. in vitro
. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
.
Abstract.
Whitehead G, Jo J, Hogg EL, Piers T, Kim D-H, Seaton G, Seok H, Bru-Mercier G, Son GH, Regan P, et al (2013). Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus.
Brain,
136(Pt 12), 3753-3765.
Abstract:
Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus.
The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca2+ -permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.
Abstract.
Author URL.
Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, Snell DM, Malpass K, Piers T, Pocock J, et al (2013). Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain, 136(4), 1067-1082.
Piers TM, Kim DH, Kim BC, Regan P, Whitcomb DJ, Cho K (2012). Translational Concepts of mGluR5 in Synaptic Diseases of the Brain. Frontiers in Pharmacology, 3
Piers TM, Heales SJ, Pocock JM (2011). Positive allosteric modulation of metabotropic glutamate receptor 5 down-regulates fibrinogen-activated microglia providing neuronal protection. Neuroscience Letters, 505(2), 140-145.
Hirano K, Piers TM, Searle KL, Miller ND, Rutter AR, Chapman PF (2009). Procognitive 5-HT6 antagonists in the rat forced swimming test: Potential therapeutic utility in mood disorders associated with Alzheimer's disease. Life Sciences, 84(15-16), 558-562.
Publications by year
In Press
Piers TM, Cosker K, Mallach A, Johnson GT, Guerreiro R, Hardy J, Pocock JM (In Press). A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia.
Abstract:
A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC--derived microglia
AbstractLoss-of-function genetic variants oftriggering receptor expressed on myeloid cells 2 (TREM2)are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2 and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on microglial metabolic function in human patient iPSC-derived-microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC-microglia, including the Alzheimer’s disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signalling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β-Amyloid phagocytosis. These findings have ramifications for microglial focussed-treatments in AD.
Abstract.
Mallach A, Gobom J, Arber C, Piers TM, Hardy J, Wray S, Zetterberg H, Pocock J (In Press). Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons.
Abstract:
Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons
AbstractMicroglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of the triggering receptor expressed myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins, and were less able to promote outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from TREM2 common variant iPS-Mg. Taken together these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47HhetTREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.Graphical Abstract
Abstract.
Cosker K, Mallach A, Limaye J, Piers TM, Staddon J, Neame SJ, Hardy J, Pocock JM (In Press). Microglial signalling pathway deficits associated with the R47H TREM2 variant linked to AD indicate inability to activate inflammasome.
Abstract:
Microglial signalling pathway deficits associated with the R47H TREM2 variant linked to AD indicate inability to activate inflammasome
AbstractThe R47H variant of the microglial membrane receptor TREM2 is linked to increased risk of late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing the AD-linked R47Hhet TREM2 variant, common variant (Cv) or an R47Hhom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction in response to the TREM2 endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling and a reduced NLRP3 inflammasome response, (including ASC speck formation, Caspase-1 activation and IL-1beta secretion). Apoptotic cell phagocytosis and soluble TREM2 shedding were unaltered, suggesting a disjoint between these pathways and the signalling cascades downstream of TREM2 in R47H-expressing iPS-Mg, whilst metabolic deficits in glycolytic capacity and maximum respiration were reversed when R47H expressing iPS-Mg were exposed to PS+ expressing cells. These findings suggest that R47H-expressing microglia are unable to respond fully to cell damage signals such as phosphatidylserine, which may contribute to the progression of neurodegeneration in late-onset AD.
Abstract.
2023
Wei J, Arber C, Wray S, Hardy J, Piers TMM, Pocock JMM (2023). Human myeloid progenitor glucocorticoid receptor activation causes genomic instability, type 1 IFN- response pathway activation and senescence in differentiated microglia; an early life stress model.
GLIA,
71(4), 1036-1056.
Author URL.
2021
Magusali N, Graham AC, Piers TM, Panichnantakul P, Yaman U, Shoai M, Reynolds RH, Botia JA, Brookes KJ, Guetta-Baranes T, et al (2021). A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the <i>OAS1</i> gene.
Brain,
144(12), 3727-3741.
Abstract:
A genetic link between risk for Alzheimer's disease and severe COVID-19 outcomes via the OAS1 gene
Abstract
. Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer’s disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known.
. Using genotyping from 1313 individuals with sporadic Alzheimer’s disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer’s disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer’s disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer’s disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-α with IFN-γ stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells.
. Collectively, our data support a link between genetic risk for Alzheimer’s disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer’s disease and COVID-19, and development of biomarkers to track disease progression.
Abstract.
Nazish I, Arber C, Piers TM, Warner TT, Hardy JA, Lewis PA, Pocock JM, Bandopadhyay R (2021). Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells. Neurochemistry International, 147, 105070-105070.
Mallach A, Gobom J, Arber C, Piers TM, Hardy J, Wray S, Zetterberg H, Pocock J (2021). Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons.
Cells,
10(11), 2866-2866.
Abstract:
Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47Hhet TREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.
Abstract.
2018
Pocock JM, Piers TM (2018). Modelling microglial function with induced pluripotent stem cells: an update. Nature Reviews Neuroscience, 19(8), 445-452.
Yi JH, Kim DH, Piers TM, Kim SC, Whitcomb DJ, Regan P, Cho K (2018). Postsynaptic p47phox regulates long-term depression in the hippocampus.
Cell Discovery,
4(1).
Abstract:
Postsynaptic p47phox regulates long-term depression in the hippocampus
AbstractIt is well documented that reactive oxygen species (ROS) affects neurodegeneration in the brain. Several studies also implicate ROS in the regulation of synapse function and learning and memory processes, although the precise source of ROS generation within these contexts remains to be further explored. Here we show that postsynaptic superoxide generation through PKCζ-activated NADPH oxidase 2 (NOX2) is critical for long-term depression (LTD) of synaptic transmission in the CA1–Shaffer collateral synapse of the rat hippocampus. Specifically, PKCζ-dependent phosphorylation of p47phox at serine 316, a NOX2 regulatory subunit, is required for LTD but is not necessary for long-term potentiation (LTP). Our data suggest that postsynaptic p47phox phosphorylation at serine 316 is a key upstream determinant for LTD and synapse weakening.
Abstract.
2015
Jebelli JD, Piers TM (2015). Amyloid-β oligomers unveil a novel primate model of sporadic Alzheimer's disease. Frontiers in Neuroscience, 9
Whitcomb DJ, Hogg EL, Regan P, Piers T, Narayan P, Whitehead G, Winters BL, Kim D-H, Kim E, St George-Hyslop P, et al (2015). Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus.
Scientific Reports,
5(1).
Abstract:
Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus
AbstractThe acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca2+-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
Abstract.
Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ (2015). Neuroprotection by safinamide in the 6‐hydroxydopamine model of <scp>P</scp>arkinson's disease.
Neuropathology and Applied Neurobiology,
42(5), 423-435.
Abstract:
Neuroprotection by safinamide in the 6‐hydroxydopamine model of Parkinson's disease
AimsCurrent therapies in Parkinson's disease mainly treat symptoms rather than provide effective neuroprotection. We examined the effects of safinamide (monoamine oxidase B and sodium channel blocker) on microglial activation and the degeneration of dopaminergic neurons in a rat model of PD
in vivo, and on microglia in vitro.MethodsRats received unilateral stereotaxic injection of 6‐hydroxydopamine into the medial forebrain bundle on day 0: the contralateral side served as control. Safinamide or vehicle was delivered from days 0 or 1, for 7 days, via sub‐cutaneous mini‐pumps.ResultsIn vehicle‐treated rats 6‐hydroxydopamine caused a significant increase in the number of activated MHC‐II+ microglia compared with the contralateral side, and only 50% of the dopaminergic neurons survived in the ipsilateral SNc. In contrast, rats treated daily with safinamide 50 and 150 mg/ml (on day 0 or 1) exhibited a significantly reduced number of activated microglia (55% reduction at 150 mg/ml) and a significant protection of dopaminergic neurons (80% of neurons survived) (P < 0.001) compared with vehicle‐treated controls. Rasagiline, a monoamine oxidase B inhibitor, and lamotrigine, a sodium channel blocking drug, also protected dopaminergic neurons, indicating that safinamide may act by either or both mechanisms. Safinamide also reduced the activation of microglial cells in response to lipopolysaccharide exposure in vitro.ConclusionSafinamide therapy suppresses microglial activation and protects dopaminergic neurons from degeneration in the 6‐hydroxydopamine model of PD, suggesting that the drug not only treats symptoms but also provides neuroprotection.
Abstract.
Jebelli J, Piers T, Pocock J (2015). Selective Depletion of Microglia from Cerebellar Granule Cell Cultures Using L-leucine Methyl Ester. Journal of Visualized Experiments(101).
Regan P, Piers T, Yi J-H, Kim D-H, Huh S, Park SJ, Ryu JH, Whitcomb DJ, Cho K (2015). Tau Phosphorylation at Serine 396 Residue is Required for Hippocampal LTD.
The Journal of Neuroscience,
35(12), 4804-4812.
Abstract:
Tau Phosphorylation at Serine 396 Residue is Required for Hippocampal LTD
Tau is required for the induction of long-term depression (LTD) of synaptic transmission in the hippocampus. Here we probe the role of tau in LTD, finding that an AMPA receptor internalization mechanism is impaired in tau KO mice, and that LTD causes specific phosphorylation at the serine 396 and 404 residues of tau. Surprisingly, we find that phosphorylation at serine 396, specifically, is critical for LTD but has no role in LTP. Finally, we show that tau KO mice exhibit deficits in spatial reversal learning. These findings underscore the physiological role for tau at the synapse and identify a behavioral correlate of its role in LTD.
Abstract.
2014
Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Brown C, Hashikawa T, Murayama M, Seok H, et al (2014). Microtubule-associated protein tau is essential for long-term depression in the hippocampus.
Philosophical Transactions of the Royal Society B: Biological Sciences,
369(1633), 20130144-20130144.
Abstract:
Microtubule-associated protein tau is essential for long-term depression in the hippocampus
. The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice
. in vivo
. and
. in vitro
. an effect that was replicated by RNAi knockdown of tau
. in vitro
. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
.
Abstract.
2013
Whitehead G, Jo J, Hogg EL, Piers T, Kim D-H, Seaton G, Seok H, Bru-Mercier G, Son GH, Regan P, et al (2013). Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus.
Brain,
136(Pt 12), 3753-3765.
Abstract:
Acute stress causes rapid synaptic insertion of Ca2+ -permeable AMPA receptors to facilitate long-term potentiation in the hippocampus.
The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca2+ -permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.
Abstract.
Author URL.
Morsali D, Bechtold D, Lee W, Chauhdry S, Palchaudhuri U, Hassoon P, Snell DM, Malpass K, Piers T, Pocock J, et al (2013). Safinamide and flecainide protect axons and reduce microglial activation in models of multiple sclerosis. Brain, 136(4), 1067-1082.
2012
Piers TM, Kim DH, Kim BC, Regan P, Whitcomb DJ, Cho K (2012). Translational Concepts of mGluR5 in Synaptic Diseases of the Brain. Frontiers in Pharmacology, 3
2011
Piers TM, Heales SJ, Pocock JM (2011). Positive allosteric modulation of metabotropic glutamate receptor 5 down-regulates fibrinogen-activated microglia providing neuronal protection. Neuroscience Letters, 505(2), 140-145.
2009
Hirano K, Piers TM, Searle KL, Miller ND, Rutter AR, Chapman PF (2009). Procognitive 5-HT6 antagonists in the rat forced swimming test: Potential therapeutic utility in mood disorders associated with Alzheimer's disease. Life Sciences, 84(15-16), 558-562.
