bioRxiv Science⌕ Search

Biology subjects

Allen, M.

Publications and source records attributed to Allen, M..

At least 37 records · Page 2Linked to original sources

Supramodal neural information supports stimulus-driven attention across cortical levels

Predictive coding posits that the brain actively anticipates inputs from different senses, generating prediction errors when incoming information deviates from internal expectations. While much research has focused on prediction errors elicited by violations of single sensory features, natural environments frequently present more complex events deviating across multiple stimulus dimensions and sensory modalities. In this study, we employed a hierarchical oddball paradigm (n=30) manipulating auditory and somatosensory stimuli to violate one or two sensory features while high-density EEG was recorded. Temporal decoding revealed that while both single- and double-deviants evoked sustained supramodal activation patterns, double-deviants uniquely elicited a supramodal response starting at 100 ms after the oddball. Effective connectivity analyses identified shared interhemispheric interactions between inferior frontal gyri across modalities, as well as distinct modality-specific connectivity within early and associative sensory cortices. Our findings demonstrate that multi-feature prediction errors recruit both rapid supramodal integration mechanisms and hierarchically organized modality-specific pathways. These results advance our understanding of how the brain flexibly integrates multiple sensory expectation violations across different levels of cortical processing, providing new insights into the neural architecture supporting predictive perception. Author summaryThe brain constantly generates predictions about incoming sensory information. While many studies focus on simple violations of individual features, real-life events often involve simultaneous deviations across multiple sensory attributes. Our goal was to examine supramodal or modality-specific aspects of multi-feature prediction errors. Considering that the cortex needs to converge individual predictions from multiple pathways for multi-feature prediction, we hypothesised that multi-feature prediction errors rely on a mid-latency supramodal process in the inferior frontal cortex. In a high-density EEG study using a nested oddball paradigm, we examined neural responses to somatosensory and auditory stimulus deviations in one or two dimensions. Using temporal decoding, we revealed an early supramodal short-lived cortical process when double-deviants are detected. We also applied Parametric Empirical Bayes Modelling to show that multi-feature prediction errors not only rely on a common interhemispheric inhibition between inferior frontal gyri but also on various supramodal and modality-specific changes in effective connectivity across associative and modality-specific cortices.

neuroscience↗

CryoET reveals actin filaments within platelet microtubules

Crosstalk between the actin and microtubule cytoskeletons is essential for many cellular processes. Recent studies have shown that microtubules and F-actin can assemble to form a composite structure where F-actin occupies the microtubule lumen. Whether these cytoskeletal hybrids exist in physiological settings and how they are formed is unclear. Here, we show that the short-crossover Class I actin filament previously identified inside microtubules in human HAP1 cells is cofilin-bound F-actin. Lumenal F-actin can be reconstituted in vitro, but cofilin is not essential. Moreover, actin filaments with both cofilin-bound and canonical morphologies reside within human platelet microtubules under physiological conditions. We propose that stress placed upon the microtubule network during motor-driven microtubule looping and sliding may facilitate the incorporation of actin into microtubules.

cell biology↗

Sex-specific effects of injury and beta-adrenergic activation on metabolic and inflammatory mediators in a murine model of post-traumatic osteoarthritis

Metabolic processes are intricately linked to the resolution of innate inflammation and tissue repair, two critical steps for treating post-traumatic osteoarthritis (PTOA). Here we used the {beta}-adrenergic receptor ({beta}AR) agonist isoproterenol as a tool to perturb intra-articular metabolism 3.5 weeks after applying a non-invasive single-load compression injury to knees of 12-week-old male and female mice. We examined the acute effects of intra-articular treatment with isoproterenol relative to saline on pain behavior, histology, multiplex gene expression, and synovial fluid metabolomics. Injured knees developed PTOA pathology characterized by heterotopic ossification, loss of tibial and femoral articular cartilage, and infrapatellar fat pad (IFP) atrophy and fibrosis. Isoproterenol modestly increased IFP atrophy and fibrosis, and it also caused sexually dimorphic and injury-dependent effects on IFP and synovium gene expression. In injured joints of female mice, isoproterenol suppressed the upregulation of pro-fibrotic genes and downregulated the expression of adipose tissue genes and pro-inflammatory genes (Adam17, Cd14, Icam1, Csf1r, and Casp1). Injury substantially altered synovial fluid metabolites by increasing amino acids, peptides, sphingolipids, phospholipids, bile acids, and dicarboxylic acids, but these changes were not appreciably altered by isoproterenol. Mechanical allodynia was also not altered by isoproterenol, although isoproterenol downregulated the expression of nociception-associated genes, Ngf and Tacr1, in injured IFP-synovium of female mice. Overall, these results suggest that {beta}AR activation functions in a sexually dimorphic manner in PTOA joints. The findings support further exploration of therapeutic strategies that target neuro-metabolic signaling pathways for treating PTOA, particularly in women.

physiology↗

Analytical Comparability to Evaluate Impact of Manufacturing Changes of ARX788, an Anti-HER2 ADC in Late-Stage Clinical Development

ARX788 is an anti-HER2 antibody drug conjugate (ADC) developed using Ambrx proprietary Engineered Precision Biologics technology. The manufacturing process of ARX788 has been optimized during the course of early to late-phase clinical development. A comprehensive evaluation of side-by-side comparability between pre- and post-change process for ARX788 drug substance and drug product from a quality perspective was conducted based on ICH Q5E guidelines consisting of batch release assays, physicochemical and biophysical characterization, biological characterization, and forced degradation studies. All results have demonstrated a high degree of similarity between the pre- and post-change ARX788 drug substance batches and drug product lots, demonstrating that the process manufacturing changes did not impact product quality.

cancer biology↗

The generation of the first chromosome-level de-novo genome assembly and the development and validation of a 50K SNP array for North American Atlantic salmon

Given the genetic and genomic differences between Atlantic salmon of European origin and North American (N.A.) origin, it is crucial to develop unique genomic resources for each lineage. Here we describe the resources that we recently developed for genomic and genetic research in N.A. Atlantic salmon. Firstly, a new single nucleotide polymorphism (SNP) database for N.A. Atlantic salmon consisting of 3.1 million putative SNPs was generated using data from whole genome resequencing of 80 N.A. Atlantic salmon individuals; Secondly, a high density 50K SNP array enriched for the genic regions of the genome and containing three sex determination and 61 continent of origin markers was developed and validated; Thirdly, a genetic map composed of 27 linkage groups with 36K SNP markers, was generated from 2,512 individuals in 141 full-sib families; Finally, a chromosome level de-novo assembly of a male N.A. Atlantic salmon genome was generated using PacBio long-reads. Information from Hi-C proximity ligation sequences and Bionano optical mapping was used to concatenate the contigs into scaffolds. The assembly contains 1,755 scaffolds and only 1,253 gaps, with a total length of 2.83 Gb and N50 of 17.2 Mb. A BUSCO analysis detected 96.2% of conserved Actinopterygii genes in the assembly and the genetic linkage information was used to guide the formation of 27 chromosome sequences. In contrast, the karyotype of the European Atlantic salmon lineage is composed of 29 chromosomes. Comparative analysis with the reference genome assembly of the European Atlantic salmon confirmed that the karyotype differences between the two linages are caused by a fission in chromosome Ssa01 and three chromosome fusions including the p arm of chromosome Ssa01 with Ssa23, Ssa08 with Ssa29 and Ssa26 with Ssa28. The genomic resources we have generated for Atlantic salmon provide a crucial boost for genetic research and for management of farmed and wild populations in this highly valued species.

genomics↗

Uncertain Precision: Neurobiological and Physiological Correlates of Conservative Confidence Bias

Correctly estimating the influence of uncertainty on our decisions is a critical metacognitive faculty. However, the relationship between sensory uncertainty (or its inverse, precision), decision accuracy, and subjective confidence is currently unclear. Although some findings indicate that healthy adults exhibit an illusion of over-confidence, under-confidence in response to sensory uncertainty has also been reported. One reason for this ambiguity is that stimulus intensity and precision are typically confounded with one another, limiting the ability to assess their independent contribution to metacognitive biases. Here we report four psychophysical experiments controlling these factors, finding that healthy human participants are systematically under-confident when discriminating low-precision stimuli. This bias remains even when decision accuracy and reaction time are accounted for, indicating that a performance-independent computation partially underpins the influence of sensory precision on confidence. We further show that this influence is linked to fluctuations in arousal and individual differences in the neuroanatomy of the left superior parietal lobe and middle insula. These results illuminate the neural and physiological correlates of precision misperception in metacognition. Significance StatementThe ability to recognize the influence of sensory uncertainty on our decisions underpins the veracity of self-monitoring, or metacognition. In the extreme, a systematic confidence bias can undermine decision accuracy and potentially underpin disordered self-insight in neuropsychiatric illness. Previously it was unclear if metacognition accurately reflects changes in sensory precision, in part due to confounding effects of stimulus intensity and precision. Here we overcome these limitations to repeatedly demonstrate a robust precision-related confidence bias. Further, we reveal novel neuroanatomical and physiological markers underlying this metacognitive bias. These results suggest a unique state-based computational mechanism may drive subjective confidence biases and further provide new avenues for investigating maladaptive awareness of uncertainty in neuropsychiatric disorders.

neuroscience↗

Functional connectivity between interoceptive brain regions is associated with distinct health-related domains - a population-based neuroimaging study

Interoception is the sensation, perception, and control of signals from within the body. It has been associated with a broad range of physiological and psychological processes. Further, interoceptive variables are related to specific regions and networks in the human brain. However, it is not clear whether or how these networks relate empirically to different domains of physiological and psychological health at the population level. We analysed a dataset of 19 020 individuals (10 055 females, 8 965 males; mean age: 63 years, age range: 45 - 81 years), who have participated in the UK Biobank Study, a very large scale prospective epidemiological health study. Using canonical correlation analysis (CCA), allowing for the examination of associations between two sets of variables, we related the functional connectome of brain regions implicated in interoception to a selection of non-imaging health and lifestyle related phenotypes, exploring their relationship within modes of population co-variation. In one integrated and data driven analysis, we obtained four statistically significant modes. Modes could be categorised into domains of affect and cardiovascular health, breathing, obesity, and subjective health (all p < 0.0001) and were meaningfully associated with distinct neural circuits. Circuits represent specific neural "fingerprints" of functional domains and set the scope for future studies on the neurobiology of interoceptive involvement in different lifestyle and health related phenotypes. Therefore, our research contributes to the conceptualisation of interoception and may lead to a better understanding of co-morbid conditions in the light of shared interoceptive structures.

neuroscience↗

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's Disease related proteins

Alzheimers disease (AD) is neuropathologically characterized by amyloid-beta (A{beta}) plaques and neurofibrillary tangles. Main protein components of these hallmarks include A{beta}40, A{beta}42, tau, phospho-tau and APOE. With the exception of the APOE-{varepsilon}4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for quantitative levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD- related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

genetics↗

Single Nuclei Transcriptome Reveals Perturbed Brain Vascular Molecules in Alzheimer's Disease

Blood-brain barrier (BBB) dysfunction is well-known in Alzheimers disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand the transcriptional changes in brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains resulting in 79,751 nuclei, 4,604 of which formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge-based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the gliovascular unit (GVU) of the BBB. Vascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid {beta} metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. Our findings provide information on transcriptional changes in predicted vascular-astrocytic partners at the GVU, bringing insights to the molecular mechanisms of BBB breakdown in AD. Graphical AbstractPericytes (yellow), endothelia (salmon) and astrocytes (purple) that form the gliovascular unit (GVU) at the blood brain barrier (BBB) were interrogated for their differentially expressed genes (DEG) and vascular cell (pericyte or endothelia) to astrocyte interactions using single nucleus RNA sequencing (RNAseq) transcriptome obtained from brains of Alzheimers disease (AD) patients and controls. We identified many upregulated (red) or downregulated (blue) DEGs in AD brains in these cell types. These genes have known biological functions in amyloid {beta} (A{beta}) clearance, immune modulation, astrogliosis and neuronal death. Novel predicted interactions were identified between vascular cells and astrocytic DEGs. Collectively, our findings highlight the vast transcriptome changes that occur at the GVU and provide mechanistic insights into BBB dysfunction in AD. This figure was created with Biorender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/474255v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@f48748org.highwire.dtl.DTLVardef@1ddc3f4org.highwire.dtl.DTLVardef@6bfa5eorg.highwire.dtl.DTLVardef@1024506_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

The landscape of metabolic brain alterations in Alzheimer's disease

INTRODUCTIONAlzheimers disease (AD) is accompanied by metabolic alterations both in the periphery and the central nervous system. However, so far, a global view of AD-associated metabolic changes in brain has been missing. METHODSWe metabolically profiled 500 samples from the dorsolateral prefrontal cortex. Metabolite levels were correlated with eight clinical parameters, covering both late-life cognitive performance and AD neuropathology measures. RESULTSWe observed widespread metabolic dysregulation associated with AD, spanning 298 metabolites from various AD-relevant pathways. These included alterations to bioenergetics, cholesterol metabolism, neuroinflammation and metabolic consequences of neurotransmitter ratio imbalances. Our findings further suggest impaired osmoregulation as a potential pathomechanism in AD. Finally, inspecting the interplay of proteinopathies provided evidence that metabolic associations were largely driven by tau pathology rather than {beta}-amyloid pathology. DISCUSSIONThis work provides a comprehensive reference map of metabolic brain changes in AD which lays the foundation for future mechanistic follow-up studies.

neuroscience↗

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimers disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in A{beta} deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

neuroscience↗

The Respiratory Resistance Sensitivity Task: An Automated Method for Quantifying Respiratory Interoception and Metacognition

The ability to sense, monitor, and control respiration - e.g., respiratory interoception (henceforth, respiroception) is a core homeostatic ability. Beyond the regulation of gas exchange, enhanced awareness of respiratory sensations is directly related to psychiatric symptoms such as panic and anxiety. Indeed, chronic breathlessness (dyspnea) is associated with a fourfold increase in the risk of developing depression and anxiety, and the regulation of the breath is a key aspect of many mindfulness-based approaches to the treatment of mental illness. Physiologically speaking, the ability to accurately monitor respiratory sensations is important for optimizing cardiorespiratory function during athletic exertion, and can be a key indicator of illness. Given the important role of respiroception in mental and physical health, it is unsurprising that there is increased interest in the quantification of respiratory psychophysiology across different perceptual and metacognitive levels of the psychological hierarchy. Compared to other more popular modalities of interoception, such as in the cardiac domain, there are relatively few methods available for measuring aspects of respiroception. Existing inspiratory loading tasks are difficult to administer and frequently require expensive medical equipment, or offer poor granularity in their quantification of respiratory-related perceptual ability. To facilitate the study of respiroception, we here present a new, fully automated and computer-controlled apparatus and psychophysiological method, which can flexibly and easily measure respiratory-related interoceptive sensitivity, bias and metacognition, in as little as 30 minutes of testing, using easy to make 3D printable parts.

neuroscience↗

Astrocytes derived from ASD patients alter behavior and destabilize neuronal activity through aberrant Ca2+ signaling

The cellular mechanisms of Autism Spectrum Disorder (ASD) are poorly understood. Cumulative evidence suggests that abnormal synapse function underlies many features of this disease. Astrocytes play in several key neuronal processes, including the formation of synapses and the modulation of synaptic plasticity. Astrocyte abnormalities have also been identified in the postmortem brain tissue of ASD patients. However, it remains unclear whether astrocyte pathology plays a mechanistic role in ASD, as opposed to a compensatory response. To address this, we strategically combined stem cell culturing with transplantation techniques to determine disease specific properties inherent to patient derived astrocytes. We demonstrate that ASD astrocytes induce repetitive behavior as well as impair memory and long-term potentiation when transplanted into the healthy mouse brain. These in vivo phenotypes were accompanied by reduced neuronal network activity and spine density caused by ASD astrocytes in hippocampal neurons in vitro. Transplanted ASD astrocytes also exhibit exaggerated Ca2+ fluctuations in chimeric brains. Genetic modulation of evoked Ca2+ responses in ASD astrocytes modulates behavior and neuronal activity deficits. Thus, we determine that ASD patient astrocytes are sufficient to induce repetitive behavior as well as cognitive deficit, suggesting a previously unrecognized primary role for astrocytes in ASD.

neuroscience↗

Genomic evidence for inter-class host transition between abundant streamlined heterotrophs by a novel and ubiquitous marine Methylophage

The methylotrophic OM43 clade are Gammaproteobacteria that comprise some of the smallest free-living cells known and have highly streamlined genomes. OM43 represents an important microbial link 0between marine primary production and remineralisation of carbon back to the atmosphere. Bacteriophages shape microbial communities and are major drivers of microbial mortality and global marine biogeochemistry. Recent cultivation efforts have brought the first viruses infecting members of the OM43 clade into culture. Here we characterize a novel myophage infecting OM43 called Melnitz. Melnitz was isolated independently on three separate occasions (with isolates sharing >99.95% average nucleotide identity) from water samples from a subtropical ocean gyre (Sargasso Sea) and temperate coastal (Western English Channel) systems. Metagenomic recruitment from global ocean viromes confirmed that Melnitz is globally ubiquitous, congruent with patterns of host abundance. Bacteria with streamlined genomes such as OM43 and the globally dominant SAR11 clade use riboswitches as an efficient method to regulate metabolism. Melnitz encodes a two-piece tmRNA (ssrA), controlled by a glutamine riboswitch, providing evidence that riboswitch use also occurs for regulation during phage infection of streamlined heterotrophs. Virally encoded tRNAs and ssrA found in Melnitz were phylogenetically more closely related to those found within the alphaproteobacterial SAR11 clade and their associated myophages than those within their gammaproteobacterial hosts. This suggests the possibility of an ancestral inter-class host transition event between SAR11 and OM43. Melnitz and a related myophage that infects SAR11 were unable to infect hosts of the SAR11 and OM43, respectively, suggesting host transition rather than a broadening of host range. IMPORTANCEIsolation and cultivation of viruses is the foundation on which the mechanistic understanding of virus-host interactions and ground-truthing is based. This study isolated and characterised the first myophage known to infect the OM43 clade, expanding our knowledge of this understudied group of microbes. The near-identical genomes of four strains of Melnitz isolated from different marine provinces and global abundance estimations from metagenomic data suggest that this viral population is globally ubiquitous. Genome analysis revealed several unusual features in Melnitz and related genomes recovered from viromes, such as a curli operon and virally encoded tmRNA controlled by a glutamine riboswitch, neither of which are found in the host. Further phylogenetic analysis of shared genes indicates that this group of viruses infecting the gammaproteobacterial OM43 shares a recent common ancestor with viruses infecting the abundant alphaproteobacterial SAR11 clade. Host ranges are affected by compatible cell surface receptors, successful circumvention of superinfection exclusion systems and the presence of required accessory proteins, which typically limits phages to singular narrow groups of closely related bacterial hosts. This study provides intriguing evidence that for streamlined heterotrophic bacteria, virus-host transitioning is not necessarily restricted to phylogenetically related hosts, but is a function of shared physical and biochemical properties of the cell.

microbiology↗

Characterising the Photoplethysmography Pulse Waveform for Use in Human Neuroscience: The Hybrid Excess and Decay (HED) Model

Photoplethysmography (PPG) offers a widely-used, convenient and non-invasive approach to monitoring basic indices of cardiovascular function such as heart rate and blood oxygenation. However, while the pulse waveform, generated by PPG comprises features that are shaped by physiological and psychological factors, it is frequently overlooked in analyses of such data. We suggest that studies could be enriched by exploiting the possibilities afforded by a systematic analysis of PPG waveforms. To do this we initially require a robust and automated means of characterising it, thereby allowing us to examine variations across individuals and between different physiological and psychological contexts. We present a psychophysiologically-relevant model, the Hybrid Excess and Decay (HED) Model, which characterises pulse wave morphology in terms of three underlying pressure waves and a decay function. We show that these parameters capture PPG data with a high degree of precision and, moreover, are sensitive to specific, physiologically-relevant changes within individuals. We present the theoretical and practical basis for the model and demonstrate its performance when applied to a pharmacological dataset of 105 participants receiving intravenous administrations of the sympathomimetic drug isoproterenol (Isoprenaline). We conclude by discussing the possible value in using the HED model to complement standard measures of PPG outputs.

neuroscience↗

DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression

Chronic myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed bulk transcriptome profiling accompanied by single cell RNA-sequencing on CD34+ stem/progenitor cells from serial patient samples obtained at the chronic MPN and sAML phases, and identified aberrantly increased expression of dual-specificity phosphatase 6 (DUSP6) underlying disease transformation. Genetic and pharmacologic targeting of DUSP6 led to inhibition of S6 and JAK/STAT signaling, resulting in potent suppression of cell proliferation, while also reducing inflammatory cytokine production in primary samples. Furthermore, ectopic DUSP6 expression augmented proliferation and mediated JAK2 inhibitor resistance, while DUSP6 inhibition reduced colony-forming potential of JAK2 inhibitor-persistent patient cells. Mechanistically, DUSP6 perturbation dampened S6 signaling via inhibition of RSK1, which we identified as a second indispensable candidate associated with poor clinical outcome. Lastly, DUSP6 inhibition potently suppressed disease development across Jak2 V617F and MPL W515L MPN mouse models, and sAML patient-derived xenografts. These findings underscore DUSP6 in driving disease transformation and therapeutic resistance, and highlight the DUSP6-RSK1 axis as a novel, druggable pathway in myeloid malignancies.

cancer biology↗

Transcriptional landscape of human microglia reveals robust gene expression signatures that implicates age, sex and APOE-related immunometabolic pathway perturbations

Microglia have fundamental roles in health and disease, however effects of age, sex and genetic factors on human microglia have not been fully explored. We applied bulk and single cell approaches to comprehensively characterize human microglia transcriptomes and their associations with age, sex and APOE. We identified a novel microglial signature, characterized its expression in bulk tissue and single cell microglia transcriptomes. We discovered microglial co-expression network modules associated with age, sex and APOE-{varepsilon}4 that are enriched for lipid and carbohydrate metabolism genes. Integrated analyses of modules with single cell transcriptomes revealed significant overlap between age-associated module genes and both pro-inflammatory and disease-associated microglial clusters. These modules and clusters harbor known neurodegenerative disease genes including APOE, PLCG2 and BIN1. Meta-analyses with published bulk and single cell microglial datasets further supported our findings. Thus, these data represent a well-characterized human microglial transcriptome resource; and highlight age, sex and APOE-related microglial immunometabolism perturbations with potential relevance in neurodegeneration.

genetics↗

Microglia show differential transcriptomic response to Aβ peptide aggregates ex vivo and in vivo

Aggregation and accumulation of amyloid-{beta} (A{beta}) is a defining feature of Alzheimers disease (AD) pathology. To study microglial responses to A{beta}, we applied exogenous A{beta} peptide, in either oligomeric or fibrillar conformation, to primary mouse microglial cultures and evaluated system level transcriptional changes and then compared these to transcriptomic changes in the brains of CRND8 APP mice. We find that primary microglial cultures have rapid and massive transcriptional change to in response to A{beta}. Transcriptomic responses to oligomeric or fibrillar A{beta} in primary microglia, though partially overlapping, are distinct and are not recapitulated in vivo where A{beta} progressively accumulates. Furthermore, though classic immune mediators show massive transcriptional changes in the primary microglial cultures, these changes are not observed in the mouse model. Together, these data extend previous studies which demonstrate that microglia responses ex vivo are poor proxies for in vivo responses. Finally, these data demonstrate the potential utility of using microglia as biosensors of different aggregate conformation, as the transcriptional responses to oligomeric and fibrillar A{beta} can be distinguished.

neuroscience↗