Biology subjects

Ruby, D. R.

Publications and source records attributed to Ruby, D. R..

2 recordsLinked to original sources

bioRxiv2026

Immune receptor LAG3 regulates microglia function duringAlzheimer's disease

Alzheimers Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 (Lag3) in a familial AD mouse model, 5xFAD+, can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD+ mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD+ mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD+ microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8+ T cell infiltration in the brain of 5xFAD+ animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions. HighlightsO_LIImmune receptor Lag3 deletion ameliorates amyloidosis and microgliosis during AD C_LIO_LILag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes C_LIO_LILag3 deletion reverses aberrant activation of DAM genes and restores microglia homeostasis C_LIO_LILag3 inhibition presents a viable approach for novel AD therapeutic interventions C_LI

neuroscience↗

bioRxiv2025

Multi-omic analyses identify molecular targets of Chd7 that mediate CHARGE syndrome model phenotypes

CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo mutations in CHD7 (chromodomain helicase DNA binding protein 7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of capgb, nefla, or rdh5 phenocopies behavioral defects seen in chd7 mutants. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome. Summary StatementWe have identified Chd7 target genes capgb, nefla, and rdh5 that mediate CHARGE model phenotypes from transcriptomic and proteomic analysis of chd7 wild type, heterozygous, and homozygous mutant zebrafish brain tissue at two developmental time points.

neuroscience↗