Biology subjects

Telpoukhovskaia, M.

Publications and source records attributed to Telpoukhovskaia, M..

5 recordsLinked to original sources

bioRxiv2026

SupeRJump: Determining normal and leukemic differentiation fate through semi-supervised jump diffusion modeling

Single cell RNA-seq (scRNA) has provided unprecedented resolution into cellular and clonal heterogeneity. Computational approaches have enabled recovery of differentiation dynamics, yet current approaches do not evaluate discontinuous differentiation processes present in malignant leukemia. To address these gaps, we developed SupeRJump: a jump-drift-diffusion based supervised cell-fate model (https://github.com/namwob44/SupeRJump/). We deploy this approach in human bone marrow, murine aging hematopoiesis, and lentivirally barcoded mouse models of acute myeloid leukemia. Our framework introduces a semi-supervised pseudotime strategy to fit a jump-drift-diffusion model and batch correction for lineage fate predictions from absorbing Markov chains. We introduce metrics to quantify a cells skewness toward particular lineages, transitions through intermediate progenitor states toward terminally differentiated states, and discontinuous transition dynamics. We use these metrics to identify cells preferentially biased for differentiation, their underlying transcriptional networks, and gene programs responsible for differentiation discontinuity.

bioinformatics↗

bioRxiv2023

Detecting the effect of genetic diversity on brain composition in an Alzheimer's disease mouse model

Alzheimers disease (AD) is characterized by neurodegeneration, pathology accumulation, and progressive cognitive decline. There is significant variation in age at onset and severity of symptoms highlighting the importance of genetic diversity in the study of AD. To address this, we analyzed cell and pathology composition of 6- and 14-month-old AD-BXD mouse brains using the semi-automated workflow (QUINT); which we expanded to allow for nonlinear refinement of brain atlas-registration, and quality control assessment of atlas-registration and brain section integrity. Near global age-related increases in microglia, astrocyte, and amyloid-beta accumulation were measured, while regional variation in neuron load existed among strains. Furthermore, hippocampal immunohistochemistry analyses were combined with bulk RNA- sequencing results to demonstrate the relationship between cell composition and gene expression. Overall, the additional functionality of the QUINT workflow delivers a highly effective method for registering and quantifying cell and pathology changes in diverse disease models.

neuroscience↗

bioRxiv2021

Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

Tau (MAPT) drives neuronal dysfunction in Alzheimers disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Taus interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Taus role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

neuroscience↗

bioRxiv2020

AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

The hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimers disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

neuroscience↗

bioRxiv2018

Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain

Microglia are resident immune cells that play critical roles in maintaining normal physiology of the central nervous system. Remarkably, microglia have intrinsic capacity to replenish after being acutely ablated. However, the underlying mechanisms that drive such microglial restoration remain elusive. Here, we removed microglia via CSF1R inhibitor PLX5622 and characterized repopulation both spatially and temporally. We also investigated the cellular origin of repopulated microglia and report that microglia are replenished via self-renewal, with little contribution from non-microglial lineage progenitors, including nestin+ progenitors and the circulating myeloid population. Interestingly, spatial analyses with multi-color labeling reveal that newborn microglia recolonize the parenchyma by forming distinctive clusters that maintain stable territorial boundaries over time, indicating proximal expansion nature of adult microgliogenesis and stability of microglia tiling. Temporal transcriptome profiling from newborn microglia at different repopulation stages revealed that the adult newborn microglia gradually regain steady-state maturity from an immature state that is reminiscent of neonatal stage and follow a series of maturation programs that include NF-{kappa}B activation, interferon immune activation and apoptosis, etc. Importantly, we show that the restoration of microglial homeostatic density requires NF-{kappa}B signaling as well as apoptotic egress of excessive cells. In summary, our study reports key events that take place from microgliogenesis to homeostasis re-establishment.

neuroscience↗