A5004262391- Neuroinflammation and Neurodegeneration Mechanisms
- Inflammation biomarkers and pathways
- Parkinson's Disease Mechanisms and Treatments
- Neurological Disease Mechanisms and Treatments
- Immune cells in cancer
- Advanced battery technologies research
- Alzheimer's disease research and treatments
- Single-cell and spatial transcriptomics
- Extracellular vesicles in disease
- Neurological diseases and metabolism
- Neurological disorders and treatments
- Adipokines, Inflammation, and Metabolic Diseases
- Metabolism and Genetic Disorders
- Atherosclerosis and Cardiovascular Diseases
- Neuroscience and Neuropharmacology Research
- Nuclear Receptors and Signaling
- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Inflammasome and immune disorders
- Medicinal Plants and Neuroprotection
University College London
2018-2024
National Hospital for Neurology and Neurosurgery
2019-2024
UK Dementia Research Institute
2023-2024
The Francis Crick Institute
2023-2024
VIB-KU Leuven Center for Brain & Disease Research
2023-2024
Queen Mary University of London
2019-2021
Imperial College London
2019
Royal Veterinary College
2017
University of London
2017
The amyloid plaque niche is a pivotal hallmark of Alzheimer's disease (AD). Here, we employ two high-resolution spatial transcriptomics (ST) platforms, CosMx and Spatial Enhanced Resolution Omics-sequencing (Stereo-seq), to characterize the transcriptomic alterations, cellular compositions, signaling perturbations in an AD mouse model. We discover heterogeneity composition niches, marked by increase microglial accumulation. profile alterations glial cells vicinity plaques conclude that...
Dysfunction of microglia, the brain's immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study consequences these variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels than primary macrophages. expression secretion were...
Abstract Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD). We investigated role primary cultures from wild type mice by using siRNA to decrease Trem2 expression, and parallel knock-in heterozygous or homozygous for R47H AD risk variant. The prevailing phenotype was decreased expression levels microglia, which resulted density microglia hippocampus. Overall, with...
The R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases risk for late onset Alzheimer's disease. Mouse models accurately reproducing phenotypes observed in Alzheimer' disease patients carrying coding are required to understand TREM2 related dysfunctions responsible enhanced A CRISPR/Cas9-assisted gene targeting strategy was used generate Trem2 knock-in mice. mRNA and protein levels as well splicing patterns were assessed these mice,...
Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk developing dementias. Microglia, the resident immune cell brain, express TREM2, and microglial responses implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely ability to undergo metabolic switch glycolysis allow them perform rapid plastic responses. We investigated role TREM2...
Abstract The R47H variant of the microglial membrane receptor TREM2 is linked to increased risk late onset Alzheimer’s disease. Human induced pluripotent stem cell derived microglia (iPS-Mg) from patient iPSC lines expressing AD-linked het variant, common (Cv) or an hom CRISPR edited line and its isogeneic control, demonstrated that R47H-expressing iPS-Mg expressed a deficit in signal transduction response endogenous ligand phosphatidylserine with reduced pSYK-pERK1/2 signalling NLRP3...
Abstract Triggering receptor on myeloid cells 2 (TREM2) is an innate immune receptor, upregulated the surface of microglia associated with amyloid plaques in Alzheimer's disease (AD). Individuals heterozygous for R47H variant TREM2 have greatly increased risk developing AD. We examined effects wild‐type (WT), and knock‐out (KO) human expression three microglial cell systems. Addition mouse BV‐2 expressing to primary neuronal cultures caused loss, not observed WT TREM2. Neuronal loss was...
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is most commonly used surgical treatment for Parkinson's disease (PD). The disease-modifying aspects DBS at a cellular level are not fully understood, and key question effect on degeneration dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc) remains to be answered. A major technical hurdle determining any neuroprotective by its use mid- late-stage patients with PD when majority DA have been lost. In this work, we...
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) associated with increased risk developing dementia. We investigated the influence TREM2 Alzheimer’s disease variant, R47Hhet, exosomal proteome consisting 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed...
Abstract Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD). We investigated role primary cultures from wild type mice by using siRNA to decrease Trem2 expression, and parallel knock-in heterozygous or homozygous for R47H AD risk variant. The prevailing phenotype was decreased expression levels microglia, which resulted density microglia hippocampus. Overall, with...
Abstract Loss-of-function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk developing dementias. Microglia, the resident immune cell brain, express TREM2 and microglial responses implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely ability to undergo metabolic switch glycolysis allow them perform rapid plastic responses. We investigated role...
<title>Abstract</title> In Alzheimer’s disease (AD) and multiple sclerosis (MS), microglia are exposed to the blood protein fibrinogen (FG), we showed previously response of primary-cultured rat FG. Here, show human iPSC-derived (iPS-Mg) respond FG, inducing secretion a range cytokines chemokines activation stress pathways. An increased pro-caspase 4/5 (and active caspase-4/5) expression was independent ER stress. Furthermore, unlike LPS/ATP which led canonical NLRP3 inflammasome pathway...
Abstract The amyloid plaque cell niche is a pivotal hallmark of Alzheimer’s disease (AD). Where early spatial transcriptomics (ST) technologies have provided valuable information on transcriptomic alterations in the small tissue domains overlaying with plaques, they lacked cellular resolution. Here we compare two novel high-resolution ST platforms, CosMx and Stereo-seq, their ability to characterize response an AD mouse model. Combining results from both techniques empowered us survey highly...
Abstract Introduction Mutations in the Leucine Rich Repeat Kinase 2 ( LRRK2 ) gene cause autosomal dominant Parkinson’s disease (PD) with most common causative mutation being p.G2019S within kinase domain. protein is highly expressed human brain and also periphery, high expression of PD genes immune cells suggest involvement microglia macrophages inflammation related to PD. known respond extracellular signalling including TLR4 resulting alterations expression, response TLR2 through zymosan...
Abstract Microglial 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) associated with increased risk developing dementia. We investigated influence TREM2 Alzheimer’s disease variant, R47H het , on exosomal proteome consisting 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content...
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause autosomal dominant Parkinson’s disease (PD), with most common causative mutation being LRRK2 p.G2019S within domain. protein is highly expressed human brain and also periphery, high expression of PD genes immune cells suggests involvement microglia macrophages inflammation related to PD. known respond extracellular signalling including TLR4, resulting alterations expression, response TLR2 through zymosan less known. Here, we...