Biology subjects

Keller, A.

Publications and source records attributed to Keller, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Angiopoietin signalling is a central axis of amyloid-driven vascular dysfunction in Alzheimer's disease

The neurovascular unit is critical for brain health, and its dysfunction has been linked to Alzheimers disease (AD). However, a cell-type-resolved understanding of how diverse vascular cells become dysfunctional and contribute to disease has been missing. Here, we applied Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to build a comprehensive transcriptomic atlas from 101 individuals along AD progression. Our analysis of over 842,646 parenchymal and vascular nuclei reveals that vascular dysfunction in AD is driven by transcriptional changes rather than shifts in cell proportions, with brain endothelial cells (BECs) and smooth muscle cells (SMCs) most affected. Strikingly, these molecular signatures emerge early at the mild cognitive impairment (MCI) stage, implicating vascular dysfunction early in AD pathogenesis. Stratifying by pathology reveals distinct vascular responses to {beta}-amyloid and tau: {beta}-amyloid burden primarily perturbs BECs and SMCs, while tau pathology predominantly impacts glial cells. We identify dysregulated angiopoietin signaling across multiple vascular cell types as a key axis, with antagonistic ANGPT2 in vascular cells and ANGPT1 in astrocytes becoming progressively dysregulated with AD. Together, this work provides a foundational resource that reveals early and pathology-specific pathways of vascular dysfunction in AD. Key MessagesO_LIVINE-seq analysis from 101 individuals creates a comprehensive human brain vascular atlas across Alzheimers disease (AD) progression. C_LIO_LIAD vascular dysfunction is driven by transcriptional changes rather than shifts in cell proportions, with BECs and SMCs most affected. C_LIO_LITranscriptional signatures of vascular dysfunction emerge early at the mild cognitive impairment (MCI) stage, preceding severe cognitive symptoms and aligning more closely with AD than cognitively normal individuals. C_LIO_LIA{beta} and tau associate with distinct vascular changes: A{beta} mainly perturbs endothelial and smooth muscle cells, while tau impacts microglia and astrocytes. C_LIO_LIAngiopoietin signaling (antagonistic ANGPT2 in vascular cells vs. ANGPT1 in astrocytes) becomes progressively dysregulated during AD progression. C_LI

neuroscience↗

bioRxiv2025

Curcumin-mediated photodynamic inactivation of Escherichia coli, Pseudomonas fluorescens, and Candida auris

Photodynamic therapy (PDT) is an emerging antimicrobial strategy that uses light to activate photosensitizers, generating reactive oxygen species (ROS) that induce microbial cell death. This study investigates the antimicrobial efficacy of curcumin-mediated PDT against the microbial pathogens Escherichia coli, Pseudomonas fluorescens, and Candida auris. The minimum inhibitory concentration (MIC) for each microorganism is determined at different light fluence rates within a clinically relevant range. Our results demonstrate that curcumin-mediated PDT effectively inactivates E. coli and C. auris, while exhibiting only partial inhibition against P. fluorescens at curcumin concentrations up to 60 {micro}M. Notably, within the tested fluence rate range, the total light dose appears to be a more critical determinant of antimicrobial efficacy than the specific fluence rate itself. The observed variations in microbial susceptibility highlight the importance of species-specific factors, such as cell wall/membrane structure. These findings provide guidelines for the application of curcumin-mediated PDT in combatting antimicrobial resistance.

microbiology↗

bioRxiv2025

ROSMAP-Compass: A data-harmonised, AI-ready atlas of 22 million single nuclei from the ROSMAP cohort

The Religious Orders Study and Memory and Aging Project (ROSMAP) cohort has generated the worlds most comprehensive single-cell transcriptomic resource for Alzheimers disease research. Naturally, in a project spanning multiple years with dozens of research groups involved, the resulting data landscape shows fragmentation across sequencing chemistries, protocols, and pipelines. This presents both a challenge and a unique opportunity for harmonized, collaborative analysis. Following an early data integration strategy and complete realignment of all single nucleus RNA sequencing data, we generated a fully harmonized resource: ROSMAP-Compass, comprising more than 22 million high-quality nuclei from 2,058 donors in multiple brain regions from the ROSMAP and Neuro Psychiatric Symptoms (NPS-AD) cohorts. Through systematic curation and unified reprocessing, we addressed substantial technical challenges including chemistry-specific biases, cross-study batch effects, and sample redundancies across multiple studies spanning different time periods and research groups. ROSMAP-Compass demonstrates the critical importance of systematic data harmonization when integrating large-scale single-cell datasets from multiple sources. By combining open science principles with cutting-edge AI integration, we provide both a critical resource for understanding Alzheimers disease heterogeneity and a blueprint for making complex biomedical data accessible to the global research community. The full resource, interactive web portal, and LLM compatible API are freely available, empowering researchers worldwide to accelerate discovery in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

PBMCpedia: A Harmonized PBMC scRNA-seq Database With Unified Mapping and Enhanced Celltype Annotation

Reproducibility in single-cell transcriptomics remains limited by inconsistent preprocessing, heterogeneous cell type annotations, and study-specific batch effects. This challenge is particularly pronounced in peripheral blood mononuclear cell (PBMC) datasets, which are central to immunological research but rarely harmonized across studies. We present PBMCpedia, a unified PBMC atlas comprising over 4.3 million single cells from 519 samples across 24 publicly available scRNA-seq studies. Unlike prior efforts, PBMCpedia reprocesses all raw sequencing data using a single, standardized pipeline with consistent quality control, batch correction, and multi-resolution cell type annotation. The dataset spans 14 diseases, including autoimmune, infectious, and neurodegenerative conditions, alongside healthy controls, enabling reproducible, metadata-aware comparisons across biological contexts. In addition to transcriptomes, PBMCpedia includes TCR/BCR repertoire data for 75 samples and surface protein measurements for 56 samples, supporting integrative immune profiling at the transcriptomic and proteogenomic levels. To support exploration and accessibility, we provide an interactive web interface (https://web.ccb.uni-saarland.de/pbmcpedia/) for querying gene expression, marker genes, and pathway enrichment across cell types, conditions, sexes, and age groups. PBMCpedia fills a critical gap by offering a transparent, harmonized, and disease-diverse PBMC resource designed for cross-study immune profiling and discovery.

bioinformatics↗

bioRxiv2025

SingleRust: A High-Performance Toolkit for Single-Cell Data Analysis at Scale

Single-cell RNA sequencing studies increasingly generate datasets exceeding 10 million cells, surpassing the memory capacity of standard analytical tools on typical institutional infrastructure. Here we introduce SingleRust, a computational framework that addresses these constraints through systematic algorithmic optimizations and systems-level design. Key improvements include sparse masked principal component analysis that reduces memory footprint while preserving biological signal, lock-free parallel implementations for differential expression testing, and adaptive k-nearest neighbor algorithms that automatically select optimal data structures based on dataset size. These optimizations achieve 2.4-25.5-fold performance improvements and 1.3-3.0-fold memory reduction compared to Scanpy, enabling routine analysis of 30 million cells on our representative test system with 512 GB RAM. Comprehensive validation confirms numerical equivalence with established methods while maintaining biological interpretation fidelity. SingleRust maintains full compatibility with the AnnData ecosystem while providing researchers immediate access to population-scale analyses on existing infrastructure, addressing a critical bottleneck in single-cell genomics workflows.

bioinformatics↗

bioRxiv2025

Extracellular vesicles and their RNA cargo facilitate bidirectional cross-kingdom communication between human and bacterial cells

While extracellular vesicles (EVs) are established mediators of intra-species signaling, their role as active participants in cross-kingdom communication remains incompletely understood. Here, we reveal that human colon cells and both Gram-positive and Gram-negative gut bacteria engage in species-specific, EV-mediated molecular dialogue, driven in part by RNA cargo. We show that bacterial EVs (BEVs) induce distinct transcriptomic responses in human cells, and that BEV-RNA independently causes similar effects. Conversely, we demonstrate that human EVs and highly abundant miR-192-5p are differentially internalized by bacteria, affecting their physiology. Our findings support a conceptual model in which EVs function as directional messengers that shape host-microbiome interactions. This study introduces a framework for understanding EVs as cross-kingdom regulators and underscores the importance of tailored, context-specific analyses for understanding the scope of EV-mediated interactions in microbiome-host homeostasis and disease. Highlights[1] L. casei, E. faecalis and P. mirabilis produce BEVs that are internalized by Caco-2 cells at different rates. BEVs produced by L. casei have a positive influence on the viability of Caco-2 cells. Incubation of Caco-2 cells with BEVs leads to changes in the gene expression of immune-response-related genes. [2] BEVs carry RNAs and the type of RNA cargo varies significantly between the BEVs from the different bacteria. Comparison of Caco-2 gene deregulation between BEVs and transfection of RNA isolated from BEV highlights component-specific effects. [3] Caco-2 EVs are taken up by E. faecalis and influence their growth. MiRNA-192-5p can be frequently detected in EVs from Caco-2 cells. Synthetic miR-192-5p is internalized by P. mirabilis and the ability to take up human miRNAs by L. casei and E. faecalis can be increased by packaging of the miRNA in artificial liposomes.

molecular biology↗

bioRxiv2025

Benchmarking Large Language Models for Pathogen-Disease Classification in Post-Acute Infection Syndromes

Post-Acute Infection Syndromes (PAIS) are medical conditions that persist following acute infections from pathogens such as SARS-CoV-2, Epstein-Barr virus, and Influenza virus. Despite growing global awareness of PAIS and the exponential increase in biomedical literature, only a small fraction of this literature pertains specifically to PAIS, making the identification of pathogen-disease associations within such a vast, heterogeneous, and unstructured corpus a significant challenge for researchers. This study evaluated the effectiveness of large language models (LLMs) in extracting these associations through a binary classification task using a curated dataset of 1,000 manually labeled PubMed abstracts. We benchmarked a wide range of open-source LLMs of varying sizes (4B-70B parameters), including generalist, reasoning, and biomedical-specific models. We also investigated the extent to which prompting strategies such as zero-shot, few-shot, and Chain of Thought (CoT) methods can improve classification performance. Our results indicate that model performance varied by size, architecture, and prompting strategy. Zero-shot prompting produced the most reliable results: Mistral-Small-Instruct-2409 and Nemotron-70B achieved balanced accuracy scores of 0.81 and 0.80, respectively, along with macro-F1 scores of up to 0.80, while maintaining minimal invalid outputs. While few-shot and CoT prompting often degraded performance in generalist models, reasoning models such as DeepSeek-R1-Distill-Llama-70B and QwQ-32B demonstrated improved accuracy and consistency when provided with additional context.

bioinformatics↗

bioRxiv2025

BAR-CAT: Targeted Recovery of Synthetic Genes via Barcode-Directed CRISPR-dCas9 Enrichment

Modern gene-synthesis platforms let us probe protein function and genome biology at unprecedented scale. Yet in large, diverse gene libraries the proportion of error-free constructs decreases with length due to the propagation of oligo synthesis errors. To rescue these rare, error-free molecules we developed BAR-CAT (Barcode-Assisted Retrieval CRISPR-Activated Targeting), an in-vitro enrichment method that couples unique PAM-adjacent 20-nt barcodes to each library member and uses multiplexed dCas9-sgRNA complexes to fish out the barcodes corresponding to perfect assemblies. After a single 15-min reaction and optimized wash regime (BAR-CAT v1.0), three low-abundance targets in a 300, 000-member test library were enriched 600-fold, greatly reducing downstream requirements. When applied to 384x and 1, 536x member DropSynth gene libraries, BAR-CAT retrieved up to 122-fold enrichment for 12 targets and revealed practical limits imposed by sgRNA competition and library complexity, which now guide ongoing protocol scaling. By eliminating laborious clone-by-clone validation and working directly on plasmid libraries, BAR-CAT provides a versatile platform for recovering perfect synthetic genes, subsetting large libraries, and ultimately lowering the cost of functional genomics at scale.

synthetic biology↗

bioRxiv2025

Nicotinic Modulation of Fast-spiking Neurons in Rat Somatosensory Cortex Across Development

Signaling at nicotinic acetylcholine receptors (nAChRs) is vital for normal development of cerebral cortical circuits. These developing circuits are also shaped by fast-spiking (FS) inhibitory cortical neurons. While nicotinic dysfunction in FS neurons is implicated in a number of psychiatric and neurodevelopmental disorders, FS neurons are thought to not have nicotinic responses in adults. Here, we establish a timeline of FS neuron response to nicotine pre- and postsynaptically in primary somatosensory cortex in male and female rats. We found that nicotine increases the frequency of spontaneous synaptic inputs to FS neurons during the second postnatal week, and this effect persisted through development. In contrast, FS neurons in S1 had no postsynaptic responses to nicotine from as early as they can be reliably identified. This was not attributable to receptor desensitization, and we further revealed that FS neurons express abundant mRNA for several nAChR subunits, beginning early in development. To determine why FS neurons do not respond to nicotine, despite expressing these receptors, we probed for the expression of lynx1, a negative nicotinic modulator. Lynx1 mRNA was expressed in FS neurons from early development, with expression increasing dramatically during the second postnatal week. SIGNIFICANCE STATEMENTSignaling at nicotinic receptors is critical for development of cortical circuits. These circuits are also shaped by fast-spiking (FS) inhibitory neurons. We reveal how these developmental processes interact, by establishing a timeline of nicotinic effects on FS neurons in rats. We find that nicotine presynaptically regulates inputs to FS neurons from early development. However, FS neurons at all ages lack postsynaptic responses to nicotine, despite expressing nicotinic receptor mRNA. This might be due to the expression of lynx1, a negative nicotinic receptor modulator, which we identify in FS neurons as early as the first postnatal week. This work reveals novel aspects of development, relevant to both normal cortical development and the neuropsychiatric pathologies associated with abnormal FS neurons and nicotinic development.

neuroscience↗

bioRxiv2025

Global Assessment of Ligation Reactions in Self-Assembled DNA Nanostructures at the Single-Nick Level

Ligation of staple strands in DNA origami nanostructures (DONs) can yield enhanced structural stability in critical environments. This process can be viewed as performing hundreds of parallel reactions programmed on a self-assembled nanoscale platform. While previous studies have focused on investigating the collective results of the chemical or enzymatic ligation reactions, herein, the global quantitative analysis of individual ligation reactions is achieved using quantitative PCR (qPCR). By mapping enzymatic ligation efficiency on a trapezoidal substructure representing one third of a triangular DON, ligation is shown to preferentially occur at the trapezoid edges rather than at inner sites. Excellent agreement between the experimental ligation yields and docking simulations suggests that this is a result of variations in the ligase docking probability. Ligation products involving more than two consecutive sequences can be generated with each enzyme-catalyzed reaction as an independent event. Interestingly, the sharp contrast between the edges vs the inner sites has been abolished by changing the reaction condition and performing the ligation in a DMSO co-solvent system. This analytic method provides unprecedented insight into the multiple ligation reactions occurring in parallel within complex DONs and will be an invaluable tool in the translation of DONs from the lab to real-world applications.

synthetic biology↗

bioRxiv2025

A cross-species rescue by mating method to interrogate gene essentiality across the Saccharomyces genus.

The field of budding yeast research has long been empowered by the vast array of genetic tools and community resources available. Rescue by mating is one useful tool that entails mating of meiotic spores directly post-germination. This minimal cell division mating process facilitates mating based screens studying the effects of otherwise haploid lethal gene deletions. In this study, we describe the successful application of rescue by mating across two different Saccharomyces species: S. cerevisiae and S. uvarum. This novel inter-species tool enables studies on the evolution of essential genes within the broader Saccharomyces genus.

genetics↗

bioRxiv2025

Synaptic proteins that aggregate and degrade slower with aging accumulate in microglia

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging1,2. We engineered bioorthogonal tools3 which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia. We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal aggregome encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia. These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.

neuroscience↗

bioRxiv2025

Lasting Increases in Neuronal Activity and Serotonergic Receptor Expression Following Gestational Chlorpyrifos Exposure

Perinatal exposure to the organophosphorus insecticide chlorpyrifos (CPF) is associated with an increased incidence of neurodevelopmental disorders, such as autism spectrum disorder. While these behavioral detriments have been modeled in rodents, the underlying functional alterations in the developing brain are largely unknown. Previous reports using a rat model have identified alterations to both inhibitory synaptic transmission and serotonergic (5-HT) receptor binding in the cortex following developmental CPF exposure. Here, we use a rat model of gestational CPF exposure to investigate whether this altered inhibitory activity is driven by increased spontaneous firing of inhibitory interneurons and altered 5-HT receptor expression. Using cell-attached ex vivo electrophysiology in young rats of both sexes, we identified a significant increase in the number of spontaneously firing neurons in the somatosensory cortex of CPF-exposed offspring. Analysis of action potential metrics identified a sub-set of these neurons as fast-spiking parvalbumin (PV) interneurons. Immunohistochemical labeling of c-Fos, a marker of neuronal activity, further revealed a pronounced increase in activity of neurons of the somatosensory cortex in both juvenile and adult rats that had been gestationally exposed to CPF. Finally, RNAscope in situ hybridization showed an increase in the expression of the inhibitory receptor 5-HT1B in PV neurons. The data here demonstrate that gestational exposure to CPF results in persistent hyper-excitation of the somatosensory cortex, potentially through increased expression of the receptor 5-HT1B and resulting disinhibition. These neurophysiological effects may contribute to the established behavioral outcomes resulting from gestational exposure to CPF and offer guidance for novel preventative interventions. SIGNIFICANCE STATEMENTWe report persistent increases in spontaneous neuronal firing in the somatosensory cortex following a brief gestational exposure to the organophosphorus insecticide CPF in rats. This occurred in conjunction with increased expression of the 5-HT1B receptor measured specifically in PV interneurons. The hyper-excitability of the somatosensory cortex described here agrees with the established hyper-sensitivity to sensory stimulation seen in neurodevelopmental disorders such as autism spectrum disorder. These results offer a possible mechanistic framework underlying the neurophysiological effects associated with early life exposures to the organophosphorus insecticide CPF.

neuroscience↗

bioRxiv2025

Assessment of Reported Error Rates in Crosslinking Mass Spectrometry

We benchmarked eight software tools in crosslinking mass spectrometry (MS) to evaluate their accuracy in detecting protein-protein interactions. Whereas about half performed reliably, others reported up to 31-fold more false interactions than indicated by their reported false discovery rates. During this community-driven effort, we helped correct one of the poorer-performing tools. Our findings demonstrate that, with robust algorithms, crosslinking MS can deliver highly dependable insights into biological systems.

bioinformatics↗

bioRxiv2025

Optimizing in-vitro Transcribed CRISPR-Cas9 single-guide RNA Libraries for Improved Uniformity and Affordability

We describe a scalable and cost-effective sgRNA synthesis workflow that reduces costs by over 70% through the use of large pools of microarray-derived oligos encoding unique sgRNA spacers. These sub-pool oligos are assembled into full-length dsDNA templates via Golden Gate Assembly before in vitro transcription with T7 RNA polymerase. RNA-seq analysis reveals severe biases in spacer representation, with some spacers being highly overrepresented while others are completely absent. Consistent with previous studies, we identify guanine-rich sequences within the first four nucleotides of the spacer, immediately downstream of the T7 promoter, as the primary driver of this bias. To address this issue, we introduced a guanine tetramer upstream of all spacers, which reduced bias by an average of 19% in sgRNA libraries containing 389 spacers. However, this modification also increased the presence of high-molecular-weight RNA species after transcription. We also tested two alternative bias-reduction strategies: compartmentalizing spacers within emulsions and optimizing DNA input and reaction volumes. Both methods independently reduced bias in 2,626-plex sgRNA libraries, though to a lesser extent than the guanine tetramer approach. These advancements enhance both the affordability and uniformity of sgRNA libraries, with broad implications for improving CRISPR-Cas9 screens and optimizing guide RNA design for other CRISPR and nuclease systems.

molecular biology↗

bioRxiv2025

Single-cell Spatial Transcriptomics Reveals Disease-specificMicroenvironmental Niches in Neurodegeneration and COVID-19

Neurodegenerative diseases and infections can produce lasting effects on brain function, yet the spatial molecular mechanisms underlying these changes remain poorly understood. Here, we present high-resolution spatial transcriptomics of 40 postmortem brain samples from patients with Parkinsons disease, frontotemporal dementia, dementia with Lewy bodies, and severe COVID-19. Analyzing over 1.5 million spatially resolved cells across dorsolateral prefrontal cortex and anterior cingulate cortex revealed disease-specific transcriptional signatures with pronounced layer-and region-specificity. In Parkinsons disease, we identified stressed neurons creating distinctive microenvironmental gradients where metabolic and protein degradation pathways are elevated near stress epicenters, while regenerative processes increase with distance. COVID-19 brains displayed extensive peripheral immune cell infiltration, particularly in the subcortical white matter, accompanied by compromised blood-brain barrier and coordinated neuroinflammatory responses from microglia, astrocytes, and endothelial cells. Integration of miRNA sequencing with spatial transcriptomics uncovered layer-specific regulatory patterns, including neuroinflammation-associated miR-155. This atlas provides unprecedented insights into disease pathology and highlights the critical importance of spatial molecular context in understanding brain disorders. Key Messages[1] A high-resolution single-cell spatial transcriptomics atlas of the dorsolateral prefrontal cortex and anterior cingulate cortex across neurodegenerative conditions and severe COVID-19 [2] Region-and layer-specific transcriptional dysregulation across disease comparisons reveals disease-specific differential vulnerability [3] Metabolically stressed cells found selectively in the anterior cingulate cortex of Parkinsons disease patients but not in dementia with Lewy bodies, along with detailed characterization of their spatial microenvironment [4] Peripheral immune cell clusters identified in the white matter of the cerebral cortex of COVID-19 patients, with detailed characterization of their spatial microenvironment [5] Integration of bulk miRNA sequencing reveals cortical layer-specific miRNA regulatory patterns

neuroscience↗

bioRxiv2025

Experimental reduction of land use increases invertebrate abundance but not diversity in grasslands

Grasslands are diverse ecosystems that are increasingly threatened by intensive land use. Restoring grasslands by reducing land-use intensity may support insect abundance and diversity, helping to halt insect declines. To test for the effect of reduced land use on invertebrates, we studied an experiment (established 2020) at 45 sites across three regions of Germany. We hypothesized that reduced land use increases invertebrate abundance and diversity, with larger effects in less intensively used grasslands. Using suction sampling, invertebrates were quantitatively sampled in May 2021 and May 2023, with 2021 samples identified by DNA meta-barcoding. Reducing land use to a single late mowing increased invertebrate abundance by 41% after one year and 99% after three years. However, species richness, Shannon diversity, and Simpson diversity did not differ between treatments and controls. Finding more individuals in grasslands with reduced land use suggests that species already present benefit, rather than additional species being recruited from the surrounding area. The effect of land-use reduction on abundance was consistently influenced by land use in the surrounding matrix, with larger positive effect sizes at grasslands with lower mowing frequency but higher fertilization. In spite of these local differences in the magnitude of restoration effects, the consistent increase in invertebrate abundance suggests that reducing land-use intensity can enhance invertebrate populations with potential benefits for ecosystem functions. It will be important to study how outcomes of land-use reduction develop over time, as land-use reduction is likely more successful when implemented permanently.

ecology↗

bioRxiv2025

A spatio-temporal brain miRNA expression atlas identifies sex-independent age-related microglial driven miR-155-5p increase

An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA (miRNA) expression across the mouse lifespan (7 time points) and two aging interventions composed of 1009 samples. MiRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and are known to mediate aging speed. We first established sex- and brain-region-specific miRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific miRNA expression changes during aging. The corpus callosum in males and the choroid plexus in females exhibited strong sex-specific age-related signatures. In this work, we identified three sex-independent brain aging miRNAs (miR-146a-5p, miR-155-5p and miR-5100). We showed for miR-155-5p that these expression changes are driven by aging microglia. MiR-155-5p targets mTOR signaling pathway components and other cellular communication pathways and is hence a promising therapeutic target.

molecular biology↗