Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes.

The forkhead transcription factor Foxj1 controls vertebrate olfactory cilia biogenesis and sensory neuron differentiation.

In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation.

transgenic line and single-cell transcriptomics reveal the origin of zebrafish intraspinal serotonergic neurons.

Sox transcription factors are crucial for vertebrate nervous system development. In zebrafish embryo, genes are expressed in neural progenitor cells and neurons of ventral spinal cord. Our recent study revealed that the loss of and function results in a significant decline of V2 subtype neurons (V2s).

RNA methyltransferase NSun2 deficiency promotes neurodegeneration through epitranscriptomic regulation of tau phosphorylation.

Epitranscriptomic regulation adds a layer of post-transcriptional control to brain function during development and adulthood. The identification of RNA-modifying enzymes has opened the possibility of investigating the role epitranscriptomic changes play in the disease process. NOP2/Sun RNA methyltransferase 2 (NSun2) is one of the few known brain-enriched methyltransferases able to methylate mammalian non-coding RNAs.

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer's Disease.

Neurogenesis is significantly reduced in Alzheimer's disease (AD) and is a potential therapeutic target. Contrary to humans, a zebrafish can regenerate its diseased brain, and thus is ideal for studying neurogenesis. To compare the AD-related molecular pathways between humans and zebrafish, we compared single cell or nuclear transcriptomic data from a zebrafish amyloid toxicity model and its controls (N = 12) with the datasets of two human adult brains (N = 10 and N = 48 (Microglia)), and one fetal brain (N = 10).

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer's Disease.

Neurogenesis decreases in Alzheimer's disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2).

Diversity and function of motile ciliated cell types within ependymal lineages of the zebrafish brain.

Motile cilia defects impair cerebrospinal fluid (CSF) flow and can cause brain and spine disorders. The development of ciliated cells, their impact on CSF flow, and their function in brain and axial morphogenesis are not fully understood. We have characterized motile ciliated cells within the zebrafish brain ventricles.

Functional properties of habenular neurons are determined by developmental stage and sequential neurogenesis.

The developing brain undergoes drastic alterations. Here, we investigated developmental changes in the habenula, a brain region that mediates behavioral flexibility during learning, social interactions, and aversive experiences. We showed that developing habenular circuits exhibit multiple alterations that lead to an increase in the structural and functional diversity of cell types, inputs, and functional modules.

Protocol for Dissection and Dissociation of Zebrafish Telencephalon for Single-Cell Sequencing.

Single-cell sequencing (sc-Seq) is a powerful tool to investigate the molecular signatures of cell types in a complex mixture of cells. A critical step in sc-Seq is preparing a single-cell suspension with a high number of viable cells. Here, we show how to dissect zebrafish telencephalon and how to dissociate it into a single-cell suspension.

Type 1 Interleukin-4 Signaling Obliterates Mouse Astroglia but Not .

Recent findings suggest that reduced neurogenesis could be one of the underlying reasons for the exacerbated neuropathology in humans, thus restoring the neural stem cell proliferation and neurogenesis could help to circumvent some pathological aspects of Alzheimer's disease. We recently identified Interleukin-4/STAT6 signaling as a neuron-glia crosstalk mechanism that enables glial proliferation and neurogenesis in adult zebrafish brain and 3D cultures of human astroglia, which manifest neurogenic properties. In this study, by using single cell sequencing in the APP/PS1dE9 mouse model of AD, we found that IL4 receptor () is not expressed in mouse astroglia and IL4 signaling is not active in these cells.

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer's model of adult zebrafish brain.

It was recently suggested that supplying the brain with new neurons could counteract Alzheimer's disease (AD). This provocative idea requires further testing in experimental models in which the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in AD and could help to understand the mechanisms to be harnessed for developing new neurons in diseased mammalian brains.

Alzheimer's disease, neural stem cells and neurogenesis: cellular phase at single-cell level.

Alzheimer's disease cannot be cured as of yet. Our current understanding on the causes of Alzheimer's disease is limited. To develop treatments, experimental models that represent a particular cellular phase of the disease and more rigorous scrutiny of the cellular pathological mechanisms are crucial.

Glia-neuron interactions underlie state transitions to generalized seizures.

Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions.

Single-Cell Transcriptomics Analyses of Neural Stem Cell Heterogeneity and Contextual Plasticity in a Zebrafish Brain Model of Amyloid Toxicity.

The neural stem cell (NSC) reservoir can be harnessed for stem cell-based regenerative therapies. Zebrafish remarkably regenerate their brain by inducing NSC plasticity in a Amyloid-β-42 (Aβ42)-induced experimental Alzheimer's disease (AD) model. Interleukin-4 (IL-4) is also critical for AD-induced NSC proliferation.

Deep sequencing reveals two Jurkat subpopulations with distinct miRNA profiles during camptothecin-induced apoptosis.

MicroRNAs (miRNAs) are small noncoding RNAs of about 19-25 nt that regulate gene expression posttranscriptionally under various cellular conditions, including apoptosis. The miRNAs involved in modulation of apoptotic events in T cells are partially known. However, heterogeneity associated with cell lines makes it difficult to interpret gene expression signatures, especially in cancer-related cell lines.

GATA3 Promotes the Neural Progenitor State but Not Neurogenesis in 3D Traumatic Injury Model of Primary Human Cortical Astrocytes.

Astrocytes are abundant cell types in the vertebrate central nervous system and can act as neural stem cells in specialized niches where they constitutively generate new neurons. Outside the stem cell niches, however, these glial cells are not neurogenic. Although injuries in the mammalian central nervous system lead to profound proliferation of astrocytes, which cluster at the lesion site to form a gliotic scar, neurogenesis does not take place.

Small RNA data set that includes tRNA-derived fragments from Jurkat cells treated with camptothecin.

In this article, we report a small RNA data set obtained from human T cell acute leukemia Jurkat cells, which were treated with the universal apoptotic agent camptothecin. Based on the Annexin-V labeling pattern, we sorted two Jurkat subpopulations in treated cells: one that is sensitive to the drug and the other being relatively more resistant. We report new original data that include the frequency of tRNA-derived fragments (tRF) in drug-sensitive and resistant cells.

Re-Arrangements in the Cytoplasmic Distribution of Small RNAs Following the Maternal-to-Zygotic Transition in Drosophila Embryos.

Small ribonucleic acids (RNAs) are known to regulate gene expression during early development. However, the dynamics of interaction between small RNAs and polysomes during this process is largely unknown. To investigate this phenomenon, 0-1 h and 7-8 h embryos were fractionated on sucrose density gradients into four fractions based on A reading (1) translationally inactive messenger ribonucleoprotein (mRNP), (2) 60S, (3) monosome, and (4) polysome.

Expressed tRNA-Derived Small RNAs Co-Sediment Primarily with Non-Polysomal Fractions in Drosophila.

Recent studies point to the existence of poorly characterized small regulatory RNAs generated from mRNAs, rRNAs and tRNAs. To explore the subcellular location of tRNA-derived small RNAs, 0-1 and 7-8 h Drosophila embryos were fractionated on sucrose density gradients. Analysis of 12,553,921 deep-sequencing reads from unfractionated and fractionated Drosophila embryos has revealed that tRFs, which are detected mainly from the 5'ends of tRNAs, co-sediment with the non-polysomal fractions.

Modeling Amyloid-β42 Toxicity and Neurodegeneration in Adult Zebrafish Brain.

Alzheimer's disease (AD) is a debilitating neurodegenerative disease in which accumulation of toxic amyloid-β42 (Aβ42) peptides leads to synaptic degeneration, inflammation, neuronal death, and learning deficits. Humans cannot regenerate lost neurons in the case of AD in part due to impaired proliferative capacity of the neural stem/progenitor cells (NSPCs) and reduced neurogenesis. Therefore, efficient regenerative therapies should also enhance the proliferation and neurogenic capacity of NSPCs.

IL4/STAT6 Signaling Activates Neural Stem Cell Proliferation and Neurogenesis upon Amyloid-β42 Aggregation in Adult Zebrafish Brain.

Human brains are prone to neurodegeneration, given that endogenous neural stem/progenitor cells (NSPCs) fail to support neurogenesis. To investigate the molecular programs potentially mediating neurodegeneration-induced NSPC plasticity in regenerating organisms, we generated an Amyloid-β42 (Aβ42)-dependent neurotoxic model in adult zebrafish brain through cerebroventricular microinjection of cell-penetrating Aβ42 derivatives. Aβ42 deposits in neurons and causes phenotypes reminiscent of amyloid pathophysiology: apoptosis, microglial activation, synaptic degeneration, and learning deficits.