Biology subjects

Priller, J.

Publications and source records attributed to Priller, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Automated quantification of white matter hyperintensity confluence: A measure of spatial organisation beyond volume and visual rating scales

White matter hyperintensities (WMH) are a highly prevalent finding on FLAIR MRI scans and a prominent feature of white matter pathology across cerebrovascular and neurodegenerative diseases. Currently, WMH are assessed with visual rating scales such as the Fazekas scale or with their volume, as calculated from automatic or manual segmentations. Both methods have limitations: Visual rating scales are rater-dependent and coarse, while WMH volume does not take the confluence of lesions into account and thus disregards their spatial organisation. As an alternative, here we propose a novel automated method for quantifying the confluence of white matter hyperintensities on a continuous standardised scale between 0 and 1. The metric is based on WMH segmentations from routine MRI and quantifies the extent to which individual WMH merge into coherent lesions, independently of total lesion volume. We apply the method to QMIN-MC, a large UK memory clinic cohort, and show associations of the confluence metric with age, cognitive performance across domains, and Fazekas ratings. Participants with vascular and mixed dementia showed higher confluence than other diagnostic groups, whereas cognitively unimpaired participants showed lower confluence. However, confluence did not explain additional cognitive variance after accounting for log-transformed WMH volume. Findings were validated in DELCODE, an independent cohort of individuals with neurodegenerative disorders, replicating our original results. In this validation cohort, periventricular WMH confluence remained associated with cognition after adjustment for WMH volume. These findings introduce WMH confluence as a reproducible, automated, and fine-grained measure of lesion spatial organisation. It provides complementary information about morphological WMH severity beyond volume and is an alternative to visual rating scales. Although related to WMH volume in memory-clinic populations, confluence captures clinically interpretable information and may complement existing WMH measures for improved lesion characterisation in studies of white matter disease, ageing, and cognitive impairment.

neuroscience↗

bioRxiv2025

Cerebrospinal fluid flow and clearance driven by lateral ventricle volume oscillations

In the human brain, substance clearance is intimately connected to the cerebrospinal fluid (CSF) and its flow. CSF extends from the lateral ventricles (LVs) to the parenchymas perivascular spaces. Macroscopic undulating CSF flow is present during both wakefulness and sleep and can be experimentally induced. However, the mechanisms generating this flow and its contribution to brain clearance remain unclear. Using fMRI and PET across various conditions, we demonstrate that LV-volume oscillations drive undulating CSF flow in the ventricles and subarachnoid basal cisternae. LV oscillations are driven by cortical blood-volume changes induced by neuronal activity, heartbeat and respiration. LV oscillations amplitudes determine PET-tracer clearance from the LVs. Conclusively, induced by extra- and intracranial physiological drivers and mediated by cortical blood-volume changes, LV-volume oscillations drive macroscopic CSF flow and clearance.

neuroscience↗

bioRxiv2025

Disrupted Forward Connectivity in Parieto-temporal Network Impairs Memory Performance in Alzheimer's Disease

Alzheimers disease (AD) is characterised by the accumulation of beta-amyloid (A{beta}) and tau proteins, leading to neurodegeneration and cognitive decline. While A{beta} and tau are known to disrupt synaptic function, the mechanisms linking these molecular pathologies to network-level dysfunction and memory impairment remain poorly understood. Here we investigated the effects of A{beta} and tau pathology (CSF A{beta}42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity (EC) related to memory encoding, which may constitute a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from participants of the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE), including 203 cognitively normal older participants (CN) as well as individuals with subjective cognitive decline (SCD; N = 204), mild cognitive impairment (MCI; N = 65), and early dementia due to AD (DAT; N = 21). EC was assessed by applying Dynamic causal modelling (DCM) to the fMRI data, using brain regions previously implicated in memory-encoding: the parahippocampal place area (PPA), the hippocampus (HC) and the precuneus (PCU). Disruptions in forward connectivity from the PPA to the HC and PCU were associated with both memory impairment and indices of AD pathology. Specifically, reduced excitatory EC from the PPA to the HC was associated with higher p-tau-181 levels and correlated with poorer memory performance. Diminished inhibitory EC from the PPA to the PCU was driven by both tau and amyloid pathology and was likewise linked to memory decline. Our findings suggest that disrupted forward connectivity within the temporo-parietal memory network constitutes a candidate mechanism mediating the relationship between molecular pathology and cognitive dysfunction.

neuroscience↗

bioRxiv2024

SMAS: Structural MRI-Based AD Score using Bayesian VAE

This study introduces the Structural MRI-based Alzheimers Disease Score (SMAS), a novel index intended to quantify Alzheimers Disease (AD)-related morphometric patterns using a deep learning Bayesian-supervised Variational Autoencoder (Bayesian-SVAE). SMAS index was constructed using baseline structural MRI data from the DELCODE study and evaluated longitudinally in two independent cohorts: DEL-CODE (n=415) and ADNI (n=190). Our findings indicate that SMAS has strong associations with cognitive performance (DELCODE: r=-0.83; ADNI: r=-0.62), age (DEL-CODE: r=0.50; ADNI: r=0.28), hippocampal volume (DEL-CODE: r=-0.44; ADNI: r=-0.66), and total grey matter volume (DELCODE: r=-0.42; ADNI: r=-0.47), suggesting its potential as a biomarker for AD-related brain atrophy. Moreover, our longitudinal studies suggest that SMAS may be useful for early identification and tracking of AD. The model demonstrated significant predictive accuracy in distinguishing cognitively healthy individuals from those with AD (DELCODE: AUC=0.971 at baseline, 0.833 at 36 months; ADNI: AUC=0.817 at baseline, improving to 0.903 at 24 months). Notably, over a 36-month period, SMAS index outperformed existing measures such as SPARE-AD and hippocampal volume. Relevance map analysis revealed significant morphological changes in key AD-related brain regions--including the hippocampus, posterior cingulate cortex, precuneus, and lateral parietal cortex--highlighting that SMAS is a sensitive and interpretable biomarker of brain atrophy, suitable for early AD detection and longitudinal monitoring of disease progression.

neuroscience↗

bioRxiv2024

Dysfunction of the episodic memory network in the Alzheimer's disease cascade

Alzheimers disease (AD) is a major cause of dementia and cognitive decline. Here we assessed how episodic memory circuit dysfunction, a hallmark of AD, is related to the longitudinal cascade of AD biomarkers, neurodegeneration and cognition using data from the DZNE Longitudinal Cognitive Impairment and Dementia study. This data set is unique by including over 1000 longitudinal functional magnetic resonance imaging (fMRI) measurements during episodic memory encoding. We leveraged a disease progression model (DPM) to obtain AD progression scores. Voxel-wise analyses revealed widespread loss of deactivation (hyperactivation) and activation (hypoactivation) with increasing disease stage. Hyperactivation trajectories were nonlinear and visually preceded trajectories of cognition. Overall, hyperactivation was independently associated with co-occurrence of amyloid- and tau-positivity and neurodegeneration, suggesting synaptic dysfunction and neurodegeneration as two independent drives of cognitive decline. Our results therefore provide evidence for a critical time window in which pharmacological treatments targeting the synapse may improve cognition.

neuroscience↗

bioRxiv2024

Human induced pluripotent stem cell-derived microglia contribute to thepathophysiology of Fragile X syndrome via increased RAC1 signaling

Fragile X syndrome (FXS) is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism and epilepsy. Emerging evidence suggests a role for immune dysfunction in autism. Using induced pluripotent stem cell (iPSC)-derived microglial cells from FXS patients (mFXS-MG) and FMR1-deficient microglia from FMR1-knock out human embryonic stem cells (FMR1 KO-MG), we show that loss-of-function of Fragile X Messenger Ribonucleoprotein (FMRP) leads to cell autonomous phagocytic deficits and a proinflammatory state in microglia when compared to gene-corrected controls. Moreover, increased RAC1 signaling in mFXS-MG and FMR1 KO-MG results in increased actin polymerization and enhanced activation of NF-{kappa}B signaling. Exposure of control iPSC-derived cortical neuron cultures to conditioned medium from proinflammatory mFXS-MG results in hyperexcitability. Importantly, pharmacological inhibition of RAC1 signaling in mFXS-MG attenuates their proinflammatory profile and corrects the neuronal hyperexcitability caused by the conditioned medium. Our results suggest that microglia impair neuronal function in FXS, which can be prevented by targeting of RAC1 signaling. Significance statementFXS is one of the most common monogenic causes of neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy and has been associated with immune dysfunction. We therefore generated brain macrophages (microglia) from patient-derived induced pluripotent stem cells (mFXS-MG) and an embryonic stem cell line deficient in the Fragile X messenger ribonucleoprotein 1 (FMR1 KO-MG). We find enhanced activation of RAC1 signaling resulting in phagocytic deficits and immune activation of mFXS-MG and FMR1 KO-MG. Exposure of control iPSC-derived cortical neurons to conditioned medium from proinflammatory mFXS-MG results in neuronal hyperexcitability, which can be prevented by pharmacological RAC1 inhibition in mFXS-MG. We conclude that RAC1 signaling in microglia could be a potential therapeutic target in FXS.

neuroscience↗

bioRxiv2024

Visually Evoked 40 Hz Gamma Activity Enhanced by Transcranial Electrical Stimulation

ObjectiveTranscranial Electrical Stimulation and Visual Stimulation in the gamma band (30-100 Hz, especially 40 Hz) are increasingly used to study and even enhance human cognition. Combining both techniques would be of scientific and clinical value, provided that Steady-State Visually Evoked Potentials (SSVEPs) are measured concurrently to determine any neuronal effects of the electrical brain stimulation. This poses a substantial methodological challenge. We aimed to demonstrate that recording visually evoked 40 Hz activity with EEG during electrical brain stimulation is possible and to explore potential interactions. ApproachWe tested if electrical and visual stimulation might interact depending on which brain areas are electrically stimulated (Experiment 1; N=25) and how closely the respective frequencies match (Experiment 2; N=25). Experiment 3 (N=25) assessed how effectively the data processing pipeline can mitigate electrical artefacts and recover real evoked neuronal activity. SSVEPs were processed and analysed in the time domain using an optimised adaptive template subtraction approach. Main Results40 Hz SSVEPs were successfully recorded during frequency-matched electrical stimulation applied between central and occipital regions. Waveform correlations revealed that SSVEPs from combined visual and electrical stimulation were more similar in shape to baseline SSVEPs from visual stimulation alone than to control data from electrical stimulation alone. Accordingly, during combined stimulation, the recovered signals were stronger in amplitude than the electrical control data. We found no evidence of interactions between electrical and visual stimulation. SignificanceWe demonstrated that 40 Hz SSVEPs can be reliably measured with EEG during frequency-matched electrical brain stimulation, distinguishing neuronal activity from electrical or physiological confounds. This method enables fundamental and clinical researchers to combine rhythmic sensory and electrical stimulation in the gamma band and concurrently quantify neuronal electrophysiological effects.

neuroscience↗

bioRxiv2024

Single-cell variations of circadian clock and immune gene expression in microglia and neurodegeneration

We investigated the diurnal rhythmicity of gene expression in microglia, the resident macrophages of the brain, in health and disease. Using RNA sequencing and single-cell analysis by RNAscope, we examined wild-type mice and the R6/2 transgenic mouse model of Huntingtons disease (HD). Our findings suggest context-dependent rhythmic gene expression in microglia, exhibiting substantial variability between individual cells and brain regions over 24 hours. Notably, we observed loss of rhythmic gene expression of key clock genes in microglia from symptomatic but not presymptomatic R6/2 mice. Moreover, we identified de novo 24-hour rhythmic gene expression and altered diurnal patterns of immune-related genes associated with neurodegenerative diseases in microglia from symptomatic R6/2 mice. Our findings suggest circadian reprogramming of microglia in the context of neurodegeneration.

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bioRxiv2023

Diagnostic images for mild cognitive impairment reveal biomarker status and abnormal scene processing

Research on the impairment of episodic memory in Alzheimers disease often focuses on the processes of memory rather than the content of the specific images being remembered. We recently showed that patients with mild cognitive impairment (MCI), Stage 3 of Alzheimers disease, can memorize certain images quite well, suggesting that episodic memory is not uniformly impaired. Certain images, on the other hand, could not be memorized by MCI patients and were instead diagnostic for distinguishing MCI from healthy older adults. In this study, we investigate whether poor memory for diagnostic images is related to impaired neural processing in specific brain regions due to Alzheimers biomarker pathology. 64 healthy controls and 48 MCI participants in the DELCODE dataset performed a visual scene memory task during fMRI, with CSF Alzheimers disease biomarker data collected (i.e., amyloid and tau biomarkers). We found that diagnostic images have larger behavior-biomarker correlations for total tau, phospho-tau, A{beta}42/A{beta}40, A{beta}42/phospho-tau compared to non-diagnostic images, suggesting that memory for these specific images are more affected by Alzheimers disease pathology. The fMRI data revealed an interaction effect between group membership (healthy control / MCI) and image diagnosticity (diagnostic / non-diagnostic scene images), with MCI participants having higher activation in scene processing regions (parahippocampal place area, retrosplenial cortex and occipital place area) for diagnostic images than non-diagnostic images. In contrast, healthy controls showed no differences in processing between diagnostic and non-diagnostic images. These results suggest that MCI individuals may engage in inefficiently heightened encoding activation for these diagnostic images. Our results show that special "diagnostic" images exist that can reveal amyloid and tau pathology and differences in neural activity in scene regions.

neuroscience↗

bioRxiv2023

Cognitive Reserve Against Alzheimer's Pathology Is Linked to Brain Activity During Memory Formation

The cognitive reserve (CR) hypothesis posits that individuals can differ in how their brain function is disrupted by pathology associated with aging and neurodegeneration. Here, we tested this hypothesis in the Alzheimers disease continuum using longitudinal data from 490 participants of the DELCODE multicentric observational study. Brain function was measured using task fMRI of visual memory encoding. Using a multivariate moderation analysis we identified a CR-related activity pattern underlying successful memory encoding that moderated the detrimental effect of AD pathological load on cognitive performance. CR was mainly represented by a more pronounced expression of the task-active network encompassing the default mode network (DMN), anterior cingulate cortex (ACC) and inferior temporal regions including the fusiform gyrus. We devised personalized fMRI-based CR scores that moderated the impact of AD pathology on cognitive performance and were positively associated with years of education. Furthermore, higher CR scores were associated with slower cognitive decline over time. Our findings suggest maintenance of core cognitive circuits including the DMN and ACC as the primary mechanism of CR. Individual brain activity levels of these areas during memory encoding have prognostic value for future cognitive decline.

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bioRxiv2023

Microglia shape hippocampal networks but are dispensable for pruning of synapses during development

Microglia, the brain-resident macrophages, are believed to sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, removing apoptotic neurons, and promoting neuronal survival. To elucidate the role of microglia during embryonic and postnatal brain development, we used a mouse model deficient in microglia throughout life as a consequence of deletion of the fms-intronic regulatory element (FIRE) in the Csf1r locus. Surprisingly, young adult Csf1r{Delta}FIRE/{Delta}FIRE mice displayed no changes in excitatory synapse number and spine density of CA1 hippocampal neurons compared to Csf1r+/+ littermates. However, CA1 neurons were less excitable, received less CA3 Schaffer collateral-mediated excitatory input and showed altered synaptic properties, but this did not affect novel object recognition. Cytokine profiling indicated an anti-inflammatory state along with increases in ApoE levels and astrocyte reactivity in brains of Csf1r{Delta}FIRE/{Delta}FIRE mice. Notably, these morphological and functional changes in Csf1r{Delta}FIRE/{Delta}FIRE mice closely resemble the effects of acute microglial depletion in adult mice that had undergone normal development. Thus, our findings challenge the prevailing view that microglia are indispensable for the establishment of neural networks during development.

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bioRxiv2023

Global neuronal activity drives cerebrospinal fluid motion mediated by brain blood volume changes in humans

In the mammalian brain, the directed motion of cerebrospinal fluid (CSF-flux) is instrumental in the distribution and removal of solutes. Changes in total cerebral blood volume (CBV) have been hypothesized to drive CSF-flux. We tested this hypothesis in two multi-modal brain imaging experiments in healthy humans, in which we drove large changes in total CBV by neuronal burst-suppression under anesthesia, or by transient global vasodilation in a hypercapnic challenge. We developed a technique to monitor CBV changes based on associated changes in total brain volume by functional MRI (fMRI) and measured cerebral blood flow by arterial spin-labeling. Relating CBV-sensitive signals to fMRI-derived measures of macroscopic CSF flow across the basal cisternae, we demonstrate that increasing total CBV extrudes CSF from the skull and decreasing CBV allows its influx. Moreover, CSF largely stagnates when CBV is stable. Together, our results establish the direct coupling between total CBV changes and CSF-flux.

neuroscience↗

bioRxiv2023

Fornix fractional anisotropy mediates the association between Mediterranean diet adherence and memory four years later in older adults without dementia

Here, we investigated whether fractional anisotropy (FA) of hippocampus-relevant white-matter tracts mediates the association between baseline Mediterranean diet adherence (MeDiAd) and verbal episodic memory over four years. Participants were healthy older adults with and without subjective cognitive decline and patients with amnestic mild cognitive impairment from the DELCODE cohort study (n = 376; age: 71.47 {+/-} 6.09 years; 48.7% female). MeDiAd and diffusion data were obtained at baseline. Verbal episodic memory was assessed at baseline and four yearly follow-ups. The associations between baseline MeDiAd and white matter, and verbal episodic memorys mean and rate of change over four years were tested with latent growth curve modeling. Baseline MeDiAd was associated with verbal episodic memory four years later (95% confidence interval, CI [0.01, 0.32]) but not with its rate of change over this period. Baseline Fornix FA mediated - and, thus, explained - that association (95% CI [0.002, 0.09]). Fornix FA may be an appropriate response biomarker of Mediterranean diet interventions on verbal memory in older adults.

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bioRxiv2022

Mapping the glial transcriptome in Huntington's disease using snRNAseq: Selective disruption of glial signatures across brain regions

Huntingtons disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from people with HD, and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of molecular chaperones represents a cross-glial signature in HD, which likely reflects an adaptive response to the accumulation of mutant Huntingtin (mHTT). Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3,5-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD brain compared to controls, which may cause dysfunction of key cellular functions due to the downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease. As glia are more tractable to treat than neurons, our findings may be of therapeutic relevance.

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bioRxiv2022

Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration

The most common genetic mutation found in familial and sporadic amyotrophic lateral sclerosis (ALS), as well as fronto-temporal dementia (FTD), is a repeat expansion in the C9orf72 gene. C9orf72 is highly expressed in human myeloid cells, and although neuroinflammation and microglial pathology are widely found in ALS/FTD, the underlying mechanisms are poorly understood. Here, using human induced pluripotent stem cell-derived microglia-like cells (hiPSC-MG) harbouring C9orf72 mutation (mC9-MG) together with gene-corrected isogenic controls (isoC9-MG) and C9ORF72 knock-out hiPSC-MG (C9KO-MG), we show that reduced C9ORF72 protein is associated with impaired phagocytosis and an exaggerated inflammatory response upon stimulation with lipopolysaccharide, driven by sustained activation of NLRP3 inflammasome and NF-{kappa}B signalling. Analysis of the hiPSC-MG C9ORF72 interactome revealed an association of C9ORF72 with key regulators of autophagy, a process involved in the homeostatic regulation of the innate immune response. We found impaired initiation of autophagy in C9KO-MG and mC9-MG. Furthermore, through motor neuron-microglial (MN-MG) co-culture studies, we identified that autophagy deficit in mC9-MG led to increased vulnerability of C9 MNs to excitotoxic stimulus. Pharmacological activation of autophagy ameliorated the sustained activation of NLRP3 inflammasome and NF-{kappa}B signalling, reversed the phagocytic deficit found in mC9-MG and also reduced MN death in MN-MG co-cultures. We validated these findings in blood-derived macrophages from people with C9orf72 mutation. Our results reveal an important role for C9ORF72 in regulating microglial immune homeostasis and identify dysregulation in human myeloid cells as a contributor to neurodegeneration in ALS/FTD. TeaserDisrupted autophagy led immune activation in microglia results in enhanced motor neuronal death in C9orf72-ALS.

neuroscience↗

bioRxiv2022

Individualized Gaussian Process-based Prediction of Memory Performance and Biomarker Status in Ageing and Alzheimer's disease

Neuroimaging markers based on Magnetic Resonance Imaging (MRI) combined with various other measures (such as informative covariates, vascular risks, brain activity, neuropsychological test etc.,) might provide useful predictions of clinical outcomes during progression towards Alzheimers disease (AD). The Bayesian approach aims to provide a trade-off by employing relevant features combinations to build decision support systems in clinical settings where uncertainties are relevant. We tested the approach in the MRI data across 959 subjects, aged 59-89 years and 453 subjects with available neuropsychological test scores and CSF biomarker status (amyloid-beta (A{beta})42/40 & and phosphorylated tau (pTau)) from a large sample multi-centric observational cohort (DELCODE). In order to explore the beneficial combinations of information from different sources, we presented a MRI-based predictive modelling of memory performance and CSF biomarker status (positive or negative) in the healthy ageing group as well as subjects at risk of Alzheimers disease using a Gaussian process multikernel framework. Furthermore, we systematically evaluated predictive combinations of input feature sets and their model variations, i.e. (A) combinations of brain tissue classes and feature type (modulated vs. unmodulated), choices of filter size of smoothing (ranging from 0 to 15 mm full width at half maximum), and image resolution (1mm, 2mm, 4mm and 8mm); (B) incorporating demography and covariates (C) the impact of the size of the training data set (i.e., number of subjects); (D) the influence of reducing the dimensions of data and (E) choice of kernel types. Finally, the approach was tested to reveal individual cognitive scores at follow-up (up to 4 years) using the baseline features. The highest accuracy for memory performance prediction was obtained for a combination of neuroimaging markers, demographics, genetic information (ApoE4) and CSF-biomarkers explaining 57% of outcome variance in out of sample predictions. The best accuracy for A{beta}42/40 status classification was achieved for combination demographics, ApoE4 and memory score while usage of structural MRI improved the classification of individual patients pTau status.

neuroscience↗

bioRxiv2021

Lifelong musical activity is associated with multi-domain cognitive and brain benefits in older adults

1AO_SCPLOWBSTRACTC_SCPLOWRegular musical activity as a highly-stimulating lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimers disease (AD). This study investigated associations between lifelong regular musical instrument playing, late-life cognitive abilities and brain morphology in older adults. We show that musical activity over the life course is associated with better global cognition, working memory, executive functions, language, and visuospatial abilities accounting for reserve proxies. Playing music is not significantly associated with gray matter volume in regions most affected by aging and AD. Selectively in the musically active participants, multi-domain cognitive abilities were enhanced with preserved gray matter volume in frontal and temporal regions. Our correlational findings suggest that playing a musical instrument may improve the recruitment of existing brain resources to facilitate late-life cognitive capacities. We propose that engaging in regular musical activity could serve as a low-threshold multimodal enrichment strategy that may promote cognitive resilience in advanced age.

neuroscience↗

bioRxiv2021

Defining the pig microglial transcriptome reveals their core signature, regional heterogeneity, and similarity with humans

Microglia play key roles in brain homeostasis as well as responses to neurodegeneration and neuroinflammatory processes caused by physical disease and psychosocial stress. The pig is a physiologically-relevant model species for studying human neurological disorders, many of which are associated with microglial dysfunction. Furthermore, pigs are an important agricultural species, and there is a need to understand how microglial function affects their welfare. As a basis for improved understanding to enhance biomedical and agricultural research, we sought to characterise pig microglial identity at genome-wide scale and conduct inter-species comparisons. We isolated pig hippocampal tissue and microglia from frontal cortex, hippocampus and cerebellum, as well as alveolar macrophages from the lungs and conducted RNA-sequencing (RNAseq). By comparing the transcriptomic profiles between microglia, macrophages, and hippocampal tissue, we derived a set of 365 highly-enriched genes defining the porcine core microglial signature. We found brain regional heterogeneity based on 215 genes showing significant (adjusted p<0.01) regional variations and that cerebellar microglia were most distinct. We compared normalized gene expression for microglia from human, mice and pigs using microglia signature gene lists derived from each species and demonstrated that a core microglial marker gene signature is conserved across species, but that species-specific expression subsets also exist. Importantly, pig and human microglia shared greater similarity than pig and murine microglia. Our data provide a valuable resource defining the pig microglial transcriptome signature that highlights pigs as a useful large animal species bridging between rodents and humans in which to study the role of microglia during homeostasis and disease. Main Points- Defined a pig microglial transcriptome signature comprising 365 genes. - Demonstrated regional variance in the pig microglial transcriptome across the brain. - Revealed greater similarity between pig and human microglia than mouse.

bioinformatics↗