Abstract
Purpose :
More women are afflicted by Alzheimer’s disease (AD) than men and carry higher neuropathological burdens. Thus, therapies that target sex-specific disease mechanisms will likely be required to effectively combat this disease. Accumulation of toxic amyloid beta protein occurs in retina prior to its emergence in the brain of AD patients and may coincide with pathological changes in visual system structure and function that also occur early in AD progression. We recently reported sex differences in patterns of early retinal amyloid accumulation and visual system dysfunction in 3xTg mice, a popular AD model with retinal amyloid accumulation. To begin identifying mechanisms for sex-related visual system vulnerability to dementia, we performed whole transcriptome analysis of microglia and astrocytes from optic nerves of female and male 3xTg mice.
Methods :
Experiment was conducted in collaboration with Nanostring Technologies. Cross-sections (6 µm) of perfusion-fixed optic nerves from 12 mo. female and male 3xTg mice were mounted on charged slides and immunostained to label microglia, astrocytes, and nuclei. Slides were incubated with a Mouse Whole Transcriptome Atlas of short, complementary RNA probes conjugated to unique, photocleavable oligonucleotide “barcodes.” Regions of interest (ROI) were automatically segmented for Iba1+ and GFAP+ nerve areas. UV light illuminated each ROI and released oligo barcodes, which were collected by automated capillary system and quantified on an nCounter platform.
Results :
Of 19,962 genes assayed, we found 11,399 with expression above our limit of quantitation. For Iba1+ ROIs, we identified 80 pathways with sex-based differential gene expression that included neuroinflammatory cytokine cascades, oxidative stress senescence pathways, integrin signaling, and lipoprotein metabolism. For GFAP+ ROIs, we found 65 pathways with differential regulation that included reactive oxygen species sensing, complement regulation, NFκB signaling, protein and lipid metabolic pathways, and cholesterol biosynthesis.
Conclusions :
Glial cells from optic nerves of female and male 3xTg AD mice showed differentially-regulated gene expression in several pathways implicated in AD pathogenesis. Data from this study suggest that differences in gliosis may underlie different sex-specific vulnerabilities in AD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.