Biology subjects

Lupton, M. K.

Publications and source records attributed to Lupton, M. K..

4 recordsLinked to original sources

bioRxiv2024

Impact of wildfire smoke and diesel exhaust on inflammatory response in aging human microglia

BackgroundAir pollution, particularly from Diesel Exhaust Particles (DEP) and Wildfire Smoke (WFS), is increasingly recognised as a significant driver of neuroinflammation linked to brain diseases. However, the role of microglia in mediating these neuroinflammatory responses remains poorly understood. This study aimed to investigate the effects of air pollution on monocyte-derived microglia-like cells (MDMi) from both young (< 40 years of age), and (older > 60 years of age) healthy individuals, focusing on immune response, cytokine secretion, nitrosative stress, and phagocytic activity. ResultsOur study demonstrated that DEP and WFS extract (WFSE) significantly upregulated expression of the oxidative stress marker, heme-oxygenase-1 (HO-1) in MDMi after 24 hr, with levels normalising by 96 hr, indicating a transient oxidative stress response. Both DEP and WFSE elicited distinct inflammatory cytokine profiles. DEP induced a rapid response, increasing TNF-, IL-6, IL-23, and IL-33 within 2 hr in young MDMi and 24 hr in aged MDMi. In contrast, WFSE triggered a delayed but sustained inflammatory response, with TNF-, IFN-{gamma}, IL-23, and IL-33 levels persisting at 96 hr in aged MDMi, highlighting an age-related vulnerability to air pollutant-induced inflammation. Both pollutants activated p38, ERK, and NF-{kappa}B pathways, with p38 activity resolving by 96 hours and ERK activation persisting, reflecting their distinct roles in cellular stress and inflammation. NF-{kappa}B p65 nuclear translocation, observed at 24 hours, highlighted its critical role in cytokine release and inflammation following exposure to DEP and WFSE. This is the first report of NF-{kappa}B activation in human microglia exposed to air pollutants. ConclusionsThese results highlight the distinct and potentially harmful effects of DEP and WFSE on immune and inflammatory responses in MDMi, particularly in ageing populations, with significant implications for brain health. DEP triggers acute oxidative stress and inflammatory responses, while WFSE induces more prolonged effects, especially in aged microglia. Both pollutants activate the MAPK and NF-{kappa}B pathways and exhibit unique cytokine profiles, underscoring their overlapping yet distinct mechanisms of action. These findings advance our understanding of air pollutant-induced neuroinflammation and its contribution to neurodegeneration, providing a foundation for developing targeted interventions to mitigate the neurotoxic effects of air pollution.

cell biology↗

bioRxiv2022

A snapshot of brain and cognition in healthy mid-life and older adults

Deficits in memory are seen as a canonical sign of ageing and a prodrome to dementia in older adults. However, the nature of cognitive and brain changes across a wider aperture of adulthood is not well known. We quantify the relationship between cognitive function and brain morphology from mid-life to older adulthood, and the influence of age, sex, amyloid and genetic risk for dementia. We analyzed three observational cohorts (PISA, AIBL, ADNI) with cognitive, genetic and neuroimaging measures comprising a total of 1570 healthy mid-life and older adults (mean age 72, range 49-90 years, 1330 males) and 1365 age- and sex-matched adults with mild cognitive impairment or Alzheimers disease. Among healthy adults, we find robust modes of co-variation between regional sulcal width and multidomain cognitive function that change from mid-life to the older age range. The most prominent cortical changes in mid-life are predominantly associated with changes in executive functions, whereas they are most strongly associated with poorer memory function in older age. These cognitive changes are accompanied by an age-dependent pattern of sulcal widening. Amyloid exerts a weak, but significant, influence on cognition, but not on sulcal width. The APOE {varepsilon}4 allele also exerts a weak influence on cognition, but only significantly in the (larger and older) AIBL cohort. These findings provide new insights into brain and cognition in mid-life and older adults, suggesting that cognitive screening in mid-life cohorts should encompass executive functions as well as memory.

neuroscience↗

bioRxiv2021

3D models of Alzheimer's disease patient microglia recapitulate disease phenotype and show differential drug responses compared to 2D

Alzheimers disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brains resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no current in vitro model system that faithfully recapitulates patient-specific microglial characteristics. To address this shortcoming, we developed novel 3D models of monocyte-derived microglia-like cells (MDMi) from AD patients. MDMi in 3D exhibited mature microglial features, including a highly branched morphology and enhanced bonafide microglial marker expression compared to 2D. Moreover, AD MDMi in 3D co-cultures with neuro-glial cells showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-{beta}. Drug screening assays in 3D AD MDMi revealed different cytokine responses compared to 2D. Our study demonstrates disease- and drug-specific responses in 3D MDMi models that are not apparent in 2D and presents a new 3D platform for more effective and personalised drug testing.

neuroscience↗

bioRxiv2020

ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression.

AimsAmyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Neuroinflammation mediated by microglial activation is evident in post-mortem brain tissues, and in brain imaging of patients with ALS. However, the exact role of microglia in ALS remains to be elucidated partly due to the lack of an accurate microglial model system that is able to recapitulate the clinical pathology of ALS. Moreover, direct sampling of microglia from patients with ALS is not feasible, further limiting the study of microglial function in ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia (MDMi) that are capable of expressing molecular markers, and functional characteristics similar to resident human brain microglia. Importantly, MDMi can be routinely and reproducibly generated from ALS patient blood, and reveal patient heterogeneity associated with age, sex and disease subgroup. MethodsMDMi were successfully established from all 30 ALS patients, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected heathy controls (HC). ResultsOur ALS MDMi model recapitulated canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive pathological inclusions. We further observed significantly impaired phagocytosis, altered cytokine expression and microglial morphology, as well as elevated DNA damage in ALS compared to HC MDMi. Abnormal phagocytosis was observed in all ALS cases, and was correlated to the progression of disease. Moreover, in-depth analysis of individual microglia revealed cell-specific variation in phagocytic function that was significantly altered, and exacerbated in rapid disease progression. ConclusionsOur approach enabled us to generate ALS patient microglia from peripheral blood samples using a rapid, robust, cost-effective, and reproducible protocol. We have shown that ALS monocyte-derived microglia have significantly altered functional behaviour compared to age-matched HCs, with a major deficit in phagocytic activity. This is also the first demonstration of abnormal TDP-43 localisation in microglia grown from ALS patients. Overall, this approach is highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents. Additionally, this model system can be used as a basis for personalised therapeutic treatment for ALS, as well as other neurodegenerative diseases.

neuroscience↗