SUN-147 - Estradiol Modulates microRNA Stability in A Female Mouse Model of Alzheimer Disease

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration resulting from toxic protein accumulation driven in part by microRNA dysregulation. MicroRNAs are small post-transcriptional regulators of gene expression that play an essential role in maintaining protein homeostasis and cellular health in the brain. Mature microRNA expression levels in the brain change with healthy aging, but emerging evidence indicates that these processes are aberrantly regulated in AD, particularly in the female brain. AD disproportionately affects women, who exhibit higher disease incidence and more rapid cognitive decline than men, a sex bias that has been linked to the sharp decrease in circulating 17-estradiol (E2) following menopause. However, the mechanisms connecting E2 decline, microRNA dysregulation, and AD pathogenesis remain poorly understood. Our previous work identified a subset of microRNAs that are regulated by E2 in an age- and brain region–specific manner, suggesting that E2 signaling may influence microRNA stability in disease-relevant pathways.
We used 3- and 9-month-old wild type (WT) and 3xTg-AD mice to test the hypothesis that the stability of E2-regulated microRNAs is altered in the context of AD. Female mice were ovariectomized and after one week, treated with E2 or vehicle for three days, followed by euthanasia. The brains were rapidly removed, flash frozen, and specific brain regions were micro dissected. Whole tissue lysates were processed using a novel microRNA degradation assay. Briefly, the lysate from each brain region was incubated with 32P-labeled microRNA oligonucleotides for varying lengths of time; the resulting full-length microRNA and their respective cleavage products were resolved using gel electrophoresis and quantified using a phosphoimager.
There was a significant effect of genotype on microRNA stability in the 3-month-old mice, well before any AD-like pathology had manifested. We also observed robust changes in microRNA stability and rates of degradation with E2 treatment, as well as brain-region-specific differences across age groups. Taken together, these findings suggest that altered microRNA stability may represent an early molecular feature of AD and could contribute to the neuroprotective actions of E2 in the brain. These dynamic changes in microRNA turnover may represent a molecular mechanism underlying the observed sex bias in AD incidence and pathology.

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