Biology subjects

Gomez-Nicola, D.

Publications and source records attributed to Gomez-Nicola, D..

7 recordsLinked to original sources

bioRxiv2024

Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterised by an increase in inflammatory cytokines and associated sickness behaviour. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may pre-condition the onset and severity of Alzheimers disease (AD)-like pathology. Our results indicate that low grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that pre-conditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in A{beta} accumulation and disease-associated microglia. These results support the notion that episodic low grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as Alzheimers disease.

neuroscience↗

bioRxiv2022

Microglial colonisation of the developing brain is facilitated by clonal expansion of highly proliferative progenitors and follows an allometric scaling

Microglia are the resident immune cells of the brain and arise from yolk sac-derived macrophages during early embryogenesis. On entering the brain, microglia undergo in situ proliferation and eventually colonise the entire brain by the second and third postnatal weeks in mice. However, the intricate dynamics of their developmental expansion remain unclear. Here, we examine and characterise the proliferative dynamics of microglia during embryonic and postnatal development. Using complementary fate-mapping techniques, we demonstrate that the developmental colonisation of the brain by microglia is facilitated by clonal expansion of highly proliferative microglial progenitors that occupy spatial niches throughout the brain. We also find that the distribution of microglia switches from a clustered to a random pattern between embryonic and late postnatal development. Moreover, the developmental increase in microglia follows the proportional growth of the brain in an allometric manner with the density of microglia eventually stabilising when the mosaic distribution has been established. Overall, our findings offer insight into how the competition for space acts as a driving force for microglial colonisation by clonal expansion during development.

neuroscience↗

bioRxiv2021

Spatiotemporal dynamics of human microglia are linked with brain developmental processes across the lifespan

Microglia, the brains resident macrophages, shape neural development and wiring, and are key neuroimmune hubs in the pathological signature of neurodevelopmental disorders. In the human brain, microglial development has not been carefully examined yet, and most of our knowledge derives from rodents. We established an unprecedented collection of 97 postmortem tissues enabling quantitative, sex-matched, detailed analysis of microglial across the human lifespan. We identify the dynamics of these cells in the human telencephalon, describing novel waves in microglial density across gestation and infancy, controlled by a balance of proliferation and apoptosis, which track key neurodevelopmental milestones. These profound changes in microglia are also observed in bulk RNAseq and single-cell RNAseq datasets. This study provides unparalleled insight and detail into the spatiotemporal dynamics of microglia across the human lifespan. Our findings serve as a solid foundation for elucidating how microglia contribute to shaping neurodevelopment in humans.

neuroscience↗

bioRxiv2021

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Abeta pathology

The sustained proliferation of microglia is a key hallmark of Alzheimers disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased {beta}gal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of A{beta} and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early A{beta} pathology in AD.

neuroscience↗

bioRxiv2020

Synaptic silencing affects the density and complexity of oligodendrocyte precursor cells in the adult mouse hippocampus

Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates OPC proliferation and differentiation. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, synaptic silencing by BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabelling for the OPC marker NG2. Inhibition of synaptic activity resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult OPC numbers and cellular integrity, which is relevant to pathological scenarios characterized by decreased synaptic activity.

neuroscience↗

bioRxiv2020

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimers disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cellular types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in neurodegenerative diseases, using the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophages populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34 and that this ligand plays an important role in the modulation of microglia population during neurodegeneration. Overall, our results suggest that control of microglial response through IL-34 blockade could be a potential therapeutic approach in neurodegenerative diseases.

neuroscience↗

bioRxiv2020

Age dependent changes in synaptic NMDA receptor composition in adult human cortical neurons

The molecular processes underlying the ageing-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in ageing synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B containing NMDARs in adult human neurons using fresh non-pathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during ageing may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

neuroscience↗