Biology subjects

Methi, A.

Publications and source records attributed to Methi, A..

4 recordsLinked to original sources

bioRxiv2025

Genetic modulation of immune gene co-expression in the aged mouse hippocampus by the Apbb1ip locus

Ageing is a major risk factor for many neurodegenerative diseases, and the hippocampus is particularly vulnerable to the effects of ageing. To define the transcriptomic changes related to ageing and the impact of genetic variation, we analysed hippocampal gene expression data generated from a genetically diverse panel of inbred mouse strains belonging to the BXD Family. We applied a combination of differential expression, differential correlation, and weighted gene co-expression network analyses, followed by genetic mapping to delineate age-associated transcriptomic patterns and genetic modulators. This study revealed an upregulation in immune response and microglial genes. We identified a key age-associated co-expression module enriched in immune related genes, and quantitative trait locus mapping of this module uncovered a genetic regulatory locus in which Apbb1ip was the primary candidate gene. Additionally, gene level differential correlation analysis identified a substantial restructuring of the hippocampal transcriptome during ageing. Notably, Ywhab, an important signalling chaperone displayed altered gene expression correlations with >70 genes, between young and aged mice. These results provide novel insights into transcriptional dynamics of hippocampal ageing and identified the immune gene Apbb1ip as a potential modulator of immune response and microglial gene upregulation with implications for neurodegenerative disease pathogenesis. HighlightsO_LIComplementary gene expression analyses indicated an upregulation of immune responses in the ageing hippocampus of a genetically diverse mouse cohort, likely driven by microglia subtypes. C_LIO_LIA systems genetics approach revealed the Apbb1ip locus as a modulator of immune gene co-expression, highlighting a novel candidate regulator of age-associated neuroimmune dynamics. C_LIO_LISignalling chaperone Ywhab gene expression was highly differentially correlated with other transcripts during ageing which may underlie widespread age-associated molecular perturbations in the hippocampus. C_LI

bioinformatics↗

bioRxiv2023

Bioengineering of a human innervated cardiac muscle model

Cardiac autonomic neurons control cardiac contractility. Dysregulation of the autonomic nervous system can lead to sympathetic overdrive resulting in heart failure and an increased incidence of fatal arrhythmias. Here, we introduce innervated engineered human myocardium (iEHM), a novel model of neuro-cardiac junctions, constructed by fusion of a bioengineered neural organoid (BENO) patterned to autonomic nervous system and engineered human myocardium (EHM). Projections of sympathetic neurons into engineered human myocardium formed presynaptic terminals in close proximity to cardiomyocytes and an extensive vascular network co-developing in the tissues. Contractile responses to optogenetic stimulation of the accordingly engineered neuronal component demonstrated functionality of neuro-cardiac junctions in iEHM. This model will serve as a human surrogate system to delineate neuron and cardiac cell contribution to brain and heart diseases and is an important step towards engineering a human brain to heart axis in a dish.

bioengineering↗

bioRxiv2023

A single-cell transcriptomic analysis of the mouse hippocampus after voluntary exercise

Exercise has been recognized as a beneficial factor for cognitive health, particularly in relation to the hippocampus, a vital brain region responsible for learning and memory. Previous research has demonstrated that exercise-mediated improvement of learning and memory in humans and rodents correlates with increased adult neurogenesis and processes related to enhanced synaptic plasticity. Nevertheless, the underlying molecular mechanisms are not fully understood. With the aim to further elucidate these mechanisms we provide a comprehensive dataset of the mouse hippocampal transcriptome at the single-cell level after four weeks of voluntary wheel-running. Our analysis provides a number of interesting observations. For example, the results suggest that exercise affects adult neurogenesis by accelerating the maturation of a subpopulation of Prdm16-expressing neurons. Moreover, we uncover the existence of an intricate crosstalk among multiple vital signaling pathways such as NF-{kappa}B, Wnt/{beta}-catenin, Notch, retinoic acid (RA) pathways altered upon exercise in a specific cluster of excitatory neurons within the Cornu Ammonis (CA) region of the hippocampus. In conclusion, our study provides an important resource dataset and sheds further light on the molecular changes induced by exercise in the hippocampus. These findings have implications for developing targeted interventions aimed at optimizing cognitive health and preventing age-related cognitive decline.

neuroscience↗

bioRxiv2023

A novel miR-99b-5p-Zbp1 pathway in microglia contributes to the pathogenesis of schizophrenia

Schizophrenia is a psychiatric disorder that is still not readily treatable. Pharmaceutical advances in the treatment of schizophrenia have mainly focused on the protein coding part of the human genome. However, the vast majority of the human transcriptome consists of non-coding RNAs. MicroRNAs are small non-coding RNAs that control the transcriptome at the systems level. In the present study we analyzed the microRNAome in blood and postmortem brains of controls and schizophrenia patients and found that miR-99b-5p was downregulated in both the prefrontal cortex and blood of patients. At the mechanistic level we show that inhibition of miR-99b-5p leads to schizophrenia-like phenotypes in mice and induced inflammatory processes in microglia linked to synaptic pruning. The miR-99b-5p-mediated inflammatory response in microglia depended on Z-DNA binding protein 1 (Zbp1) which we identified as a novel miR-99b-5p target. Antisense oligos (ASOs) against Zbp1 ameliorated the pathological phenotypes caused by miR-99b-5p inhibition. In conclusion, we report a novel miR-99b-5p-Zbp1 pathway in microglia that contributes to the pathogenesis of schizophrenia. Our data suggest that strategies to increase the levels of miR-99b-5p or inhibit Zbp1 could become a novel therapeutic strategy.

neuroscience↗