Vierling, T. T. | Search bioRxiv

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↗

bioRxiv2024

Identification of hippocampal area CA2 in hamster and vole brain

Prairie voles (Microtus ochrogaster) and Syrian, or golden, hamsters (Mesocricetus auratus) are closely related to mice (Mus musculus) and rats (Rattus norvegicus, for example) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. The CA2 region of the hippocampus is known to play a key role in social memory and aggression in mice and responds to social stimuli in rats, likely owing to its high expression of oxytocin and vasopressin 1b receptors. However, CA2 has yet to be identified and characterized in hamsters or voles. In this study, we sought to determine whether CA2 could be identified molecularly in vole and hamster. To do this, we used immunofluorescence with primary antibodies raised against known molecular markers of CA2 in mice and rats to stain hippocampal sections from voles and hamsters in parallel with those from mice. Here, we report that, like in mouse and rat, staining for many CA2 proteins in vole and hamster hippocampus reveals a population of neurons that express regulator of G protein signaling 14 (RGS14), Purkinje cell protein 4 (PCP4) and striatal-enriched protein tyrosine phosphatase (STEP), which together delineate the borders with CA3 and CA1. These cells were located at the distal end of the mossy fiber projections, marked by the presence of Zinc Transporter 3 (ZnT-3) and calbindin in all three species. In addition to staining the mossy fibers, calbindin also labeled a layer of CA1 pyramidal cells in mouse and hamster but not in vole. However, Wolframin ER transmembrane glycoprotein (WFS1) immunofluorescence, which marks all CA1 neurons, was present in all three species and abutted the distal end of CA2, marked by RGS14 immunofluorescence. Staining for two stress hormone receptors--the glucocorticoid (GR) and mineralocorticoid (MR) receptors--was also similar in all three species, with GR staining found primarily in CA1 and MR staining enriched in CA2. Interestingly, although perineuronal nets (PNNs) are known to surround CA2 cells in mouse and rat, we found that staining for PNNs differed across species in that both CA2 and CA3 showed staining in voles and primarily CA3 in hamsters with only some neurons in proximal CA2 showing staining. These results demonstrate that, like in mouse, CA2 in voles and hamsters can be molecularly distinguished from neighboring CA1 and CA3 areas, but PNN staining is less useful for identifying CA2 in the latter two species. These findings reveal commonalities across species in molecular profile of CA2, which will facilitate future studies of CA2 in these species. Yet to be determined is how differences in PNNs might relate to differences in social behavior across species.

neuroscience↗