Marina A Lynch

Marina A Lynch
Trinity College Dublin | TCD · Institute of Neuroscience

PhD

About

333
Publications
18,262
Reads
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18,514
Citations
Citations since 2016
29 Research Items
6434 Citations
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201620172018201920202021202202004006008001,000
201620172018201920202021202202004006008001,000
Additional affiliations
December 1992 - present
Trinity College
Position
  • Professor of Cellular Neuroscience
December 1992 - present
Trinity College Dublin
Position
  • Professor of Cellular Neuroscience
Description
  • Neuroinflammation. Microglial activation in age and models of AD

Publications

Publications (333)
Article
Full-text available
Many studies implicate microglia in the pathogenesis of Alzheimer’s disease (AD) but precisely how these cells make their impact has not been determined to date. One contributory factor is likely to be the enhanced production of inflammatory mediators and it is now known that microglia with this secretory phenotype exhibit other adaptations includi...
Article
Full-text available
One area of microglial biology that has been relatively neglected until recently is sex differences and this is in spite of the fact that sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. Why these sex differences exist is not known but the panoply of differences extend to...
Article
Full-text available
There is a striking sex-related difference in the prevalence of many neurodegenerative diseases, highlighting the need to consider whether treatments may exert sex-specific effects. A change in microglial activation state is a common feature of several neurodegenerative diseases and is considered to be a key factor in driving the inflammation that...
Article
Full-text available
Age and sex are major risk factors in Alzheimer’s disease (AD) with a higher incidence of the disease in females. Neuroinflammation, which is a hallmark of AD, contributes to disease pathogenesis and is inexorably linked with inappropriate microglial activation and neurodegeneration. We investigated sex-related differences in microglia in APP/PS1 m...
Article
Full-text available
Neuroinflammation is now recognised as an important contributory factor in the progression of Alzheimer’s disease and probably also in the early stages of the disease. It is likely that this derives largely from aberrant activation of microglia, the resident mononuclear phagocytes of the brain. These cells are responsible for physiological immune s...
Article
Microglial activation and neuroinflammatory changes are characteristic of the aged brain and contribute to age-related cognitive impairment. Exercise improves cognitive function in aged animals, perhaps because of a modulatory effect on microglial activation. Recent evidence indicates that inflammatory microglia are glycolytic, driven by an increas...
Article
The search for a blood-based biomarker that identifies Alzheimer's disease (AD) and can replace current invasive and expensive diagnostic tests, continues. The most extensively-examined peripheral marker is β-amyloid (Aβ) but the results are inconsistent across studies and do not reflect the changes that take place in the brain. Several studies hav...
Article
In the past few years it has become increasingly clear that an understanding of the interaction between metabolism and immune function can provide an insight into cellular responses to challenges. Significant progress has been made in terms of how macrophages are metabolically re-programmed in response to inflammatory stimuli but, to date, little e...
Article
Full-text available
Inflammation and metabolism are intricately linked during inflammatory diseases in which activation of the nucleotide-binding domain–like receptors Family Pyrin Domain Containing 3 (NLRP3) inflammasome, an innate immune sensor, is critical. Several factors can activate the NLRP3 inflammasome, but the nature of the link between NLRP3 inflammasome ac...
Article
Among the changes that typify Alzheimer's disease (AD) are neuroinflammation and microglial activation, amyloid deposition perhaps resulting from compromised microglial function, and iron accumulation. Data from Genome Wide Association Studies (GWAS) identified a number of gene variants that endow a significant risk of developing AD and several of...
Article
Full-text available
Background: Microglia are multifunctional cells that are primarily neuroprotective and a deficit in their functional integrity is likely to be a contributory factor in the deteriorating neuronal function that occurs with age and neurodegeneration. One aspect of microglial dysfunction is reduced phagocytosis, and this is believed to contribute to t...
Article
Identification of a blood-based biomarker that can detect early cognitive decline presents a significant healthcare challenge. We prepared peripheral blood mononuclear cells (PBMCs) from individuals who had a poorer than predicted performance in their delayed recall performance on the Logical Memory II Subtest of the Wechsler Memory Scale (WMS) rel...
Article
Full-text available
It is well established that infection has a significant detrimental effect on patients with Alzheimer's disease (AD), accelerating cognitive decline and, even in healthy ageing individuals, increasing amyloid-β (Aβ) accumulation in the brain. In animal models of AD infection can also cause damage, with evidence of increased neuroinflammation, amylo...
Article
Microglia, like macrophages, can adopt inflammatory and anti-inflammatory phenotypes depending on the stimulus. In macrophages, the evidence indicates that these phenotypes have different metabolic profiles with lipopolysaccharide (LPS)- or interferon-γ (IFNγ)-stimulated inflammatory cells switching to glycolysis as their main source of ATP and int...
Article
Full-text available
One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is obs...
Article
Full-text available
Th1 and Th17 cells have an established role in protective immunity to Bordetella pertussis, but this evidence is based largely on peripheral T cells. There is emerging evidence that local tissue-resident memory T (TRM) cells that accumulate in tissue following mucosal infection may be crucial for long-term immunity. In this study, we examined the r...
Poster
INHIBITING TLR2 ACTIVATION ATTENUATES AMYLOID ACCUMULATION AND GLIAL ACTIVATION IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Article
Activation of the inflammasome is implicated in the pathogenesis of an increasing number of inflammatory diseases, including Alzheimer's disease (AD). Research reporting inflammatory changes in post mortem brain tissue of individuals with AD and GWAS data have convincingly demonstrated that neuroinflammation is likely to be a key driver of the dise...
Article
Potential associations between systemic inflammation and social support received by a sample of 120 older adults were examined here. Inflammatory markers, cognitive function, social support and psychosocial wellbeing were evaluated. A structural equation modelling approach was used to analyse the data. The model was a good fit χ 108 2 = 256 . 13...
Article
The effects of Toll-like receptor (TLR) activation in peripheral cells are well characterized but, although several TLRs are expressed on cells of the brain, the consequences of their activation on neuronal function remain to be fully investigated, particularly in the context of assessing their potential as therapeutic targets in neurodegenerative...
Article
Full-text available
Ageing is a complex multifactorial process that results in many changes in physiological changes processes that ultimately increase susceptibility to a wide range of diseases. As such an ageing population is resulting in a pressing need for more and improved treatments across an assortment of diseases. Such treatments can come from a better underst...
Article
Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4(th) Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9(th) May 2015, presenting updates on innate immunity in...
Article
The impact of infiltration of macrophages into the brain is debatable with evidence of both beneficial and detrimental effects. Recent work suggests that inflammatory macrophages, with an inflammatory phenotype that resembles the M1 activation state, may be detrimental, whereas anti-inflammatory M2-like macrophages may be beneficial. We set up a mo...
Chapter
Neurodegenerative diseases share a number of common features with respect to clinical course, pathology, and molecular mechanisms. This chapter outlines the common themes of neurodegeneration, including the concept of selective neuronal vulnerability, genetic susceptibility, aberrant protein structures, disruption in mitochondrial function, altered...
Article
The overly-simplistic view that inflammatory and anti-inflammatory influences in the brain were respectively detrimental and advantageous in Alzheimer's disease (AD) is being challenged by advances in methodologies, and a debate relating to immune surveillance mechanisms in the brain. In contrast with previous findings, increasing interleukin (IL)-...
Article
There is a wealth of evidence indicating that macrophages adopt distinct phenotypes when exposed to specific stimuli and, in the past few years, accumulating data suggest that microglia behave somewhat similarly. Therefore, microglia can adopt the so-called M1 or M2 phenotypes in response to interferon-γ (IFNγ) and interleukin-4, respectively. Alth...
Article
Macrophages can be polarised to adopt the M1 or M2 phenotype and functional outcomes of activation include altered secretion of immune molecules such as insulin-like growth factor (IGF)-1 as well as upregulation of cell surface molecules specifically associated with each state. Interleukin (IL)-4 mediates its effects through two receptors, the type...
Article
Alzheimer's disease (AD) is the most common cause of dementia, and is characterised by deposits of amyloid β (Aβ), neurofibrillary tangles and neuronal loss. Neuroinflammatory changes have been identified as a feature of the disease, and recent studies have suggested a potential role for the peripheral immune system in driving these changes and, ul...
Article
Full-text available
Background Lipopolysaccharide (LPS) and interferon-γ (IFNγ) increase expression of tumour necrosis factor-α (TNFα) that characterizes the M1 activation state of macrophages. Whereas it is accepted that the immune system undergoes changes with age, there is inconsistency in the literature with respect to the impact of age on the response of macropha...
Article
The immunoregulatory function of single-Ig-interleukin-1 related receptor (SIGIRR) is derived from its ability to constrain the inflammatory consequences of interleukin (IL)-1R and toll-like receptor (TLR)4 activation. This role extends to the brain, where SIGIRR deficiency increases the synaptic and cognitive dysfunction associated with IL-1R- and...
Article
Full-text available
Macrophages are key cells in tissue defense in the periphery and, under certain circumstances, infiltrate the central nervous system, where they may play a similar role in the brain, perhaps supporting the function of microglia. Macrophages have been shown to adopt different activation states in response to various stimuli. Specifically, when expos...
Article
The role of IFN-γ in the pathogenesis of autoimmune diseases is controversial. Although Th1 cells can induce experimental autoimmune encephalomyelitis (EAE), IFN-γ can suppress Th17 cells that are pathogenic in EAE. Here we show that NK cells provide an early source of IFN-γ during development of EAE. Depletion of NK cells or neutralization of IFN-...
Article
Full-text available
The intestinal microbiota is increasingly recognized as a complex signaling network that impacts on many systems beyond the enteric system modulating, among others, cognitive functions including learning, memory and decision-making processes. This has led to the concept of a microbiota-driven gut-brain axis, reflecting a bidirectional interaction b...
Article
In recent years it has become clear that neuroinflammatory changes develop in the brain with age and that similar, though more profound changes, occur in neurodegenerative conditions and in animal models of neurodegeneration. These changes are linked with deterioration in plasticity and the evidence suggests that a key causative factor is microglia...
Article
Microglia are particularly plastic cells which can be shifted from their resting state by numerous factors and adopt distinct phenotypes. The cells are multifunctional, though their main role is probably maintenance of homoeostasis. Resting cells are responsible for surveillance, whereas activation induces the cells to adopt neuroprotective or neur...
Article
Aging adversely affects inflammatory processes in the brain, which has important implications in the context of disease progression. It has been proposed that microglia become dysfunctional with age and may lose their neuroprotective properties leading to chronic neurodegeneration. Here, we sought to characterize inflammatory changes in a mouse mod...
Article
Full-text available
The NLRP3 inflammasome forms in response to a diverse range of stimuli and is responsible for the processing and release of interleukin-1β (IL-1β) from the immunocompetent cells of the brain. The pathological peptide of Alzheimer's disease, amyloid beta (Aβ), induces formation of the NLRP3 inflammasome in a manner dependent on the family of proteas...
Article
The interaction between CD200, expressed on several cell types, and its receptor CD200R, expressed on cells of the myeloid lineage, has been shown to be an important factor in modulating inflammation in macrophage function in several conditions including colitis and arthritis. More recently its modulatory effect on microglial activation has been id...
Article
The family of toll-like receptors (TLR) plays a major role in innate immunity due to their pathogen-recognition abilities. TLR3 is a sensor for double-stranded RNA, and regulates host-defense responses to several viruses, via the production of type I interferons. Interferon-β (IFNβ) is a primary product of TLR3 activation, and its transcription is...
Article
Neuroinflammatory changes are a characteristic of several, if not all, neurodegenerative diseases including Alzheimer's disease (AD) and are typified by increased microglial activation. Microglia express several receptors making them highly reactive and plastic cells, and, at least in vitro, they adopt different phenotypes in a manner analogous to...
Article
Whereas the classical histological hallmarks of Alzheimer's disease (AD) are deposition of amyloid-containing plaques and development of neurofibrillary tangles, there is also clear evidence of inflammatory changes accompanied by the presence of activated microglia and astrocytosis. However, at this time, it remains uncertain whether inflammatory c...
Article
Accumulating evidence continues to underpin the role of the innate immune system in pathologies associated with neuroinflammation. Innate immunity is regulated by pattern recognition receptors that detect pathogens and, in the case of Gram-positive bacteria, binding of bacterial lipopeptides to toll-like receptor (TLR)2 is emerging as an important...
Article
Full-text available
Cells of the innate immune system including monocytes and macrophages are the first line of defence against infections and are critical regulators of the inflammatory response. These cells express toll-like receptors (TLRs), innate immune receptors which govern tailored inflammatory gene expression patterns. Monocytes, which produce pro-inflammator...
Data
Flow cytometric analysis of MDMs. Flow cytometric analysis of MDMs and selection of CD14+ cells. CD14+ monocytes were separated from PBMCs using a MACS sorter. The CD14+ monocytes were cultured for 7 days with GM-CSF (10 ng/ml), and stained with a CD14 antibody to determine purity by flow cytometry. Gates were made using the isotype controls. After...
Data
Flow cytometric analysis of PBMCs. A) Flow cytometric analysis of PBMCs and selection of live cells. PBMC gate location determined via forward/side scatter analysis of PBMCs. B) Using a logical gating strategy, live PBMCs gated for CD11b. (TIF)
Article
Alzheimer's disease (AD) is characterized by the presence of amyloid-β (Aβ)-containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aβ plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis...
Article
Fibroblast growth loop (FGL) is a neural cell adhesion molecule (NCAM)-mimetic peptide that mimics the interaction of NCAM with fibroblast growth factor receptor (FGFR). FGL increases neurite outgrowth and promotes neuronal survival in vitro, and it has also been shown to have neuroprotective effects in vivo. More recent evidence has indicated that...
Article
Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis and its induction is associated with the infiltration of encephalitogenic T cells into the CNS. Autoantigen-specific IL-17-producing Th17 cells and IFN-γ-producing Th1 cells are central to the pathogenesis of EAE. However, cells of the innate immune...
Article
Astrocytes, the most numerous glial cell in the brain, have multiple functions and are key to maintenance of homeostasis in the central nervous system. Microglia are the resident immunocompetent cells in the brain and share several functions with macrophages, including their phagocytic ability. Indeed microglia are the resident phagocytes in the br...
Article
Full-text available
The neural cell adhesion molecule, NCAM, is ubiquitously expressed within the CNS and has roles in development, cognition, neural plasticity and regulation of the immune system. NCAM is thus potentially an important pharmacological target for treatment of brain diseases. A cell adhesion mimetic FGL, a 15 amino-acid peptide derived from the second f...
Article
The P2X(7) receptor is an ion-gated channel, which is activated by high extracellular concentrations of adenosine triphosphate (ATP). Activation of P2X(7) receptors has been shown to induce neuroinflammatory changes associated with several neurological conditions. The matrix metalloproteinases (MMPs) are a family of endopeptidases that have several...