SUN-112 - Establishing A Model for Post-Menopausal Risk of Neurodegeneration through Aromatase Inhibition in Mice.

Estrogens, though often regarded in the reproductive system, exert profound effects on the central nervous system (CNS) and may play a role in increased risk of disease in post-menopausal, estrogen-deficient females. Aromatase works as the main driver of estrogen synthesis in the brain, converting androstenedione and testosterone into estrone and estradiol, two of the main forms of estrogen in the body. Aromatase is an enzyme encoded by the CYP19A1 gene and is widely expressed in a subpopulation of neurons, astrocytes, and other CNS cell types. Estradiol produced locally regulates cellular signaling, gene expression, synaptic transmission and synaptic plasticity—all crucial for cellular health and defenses against neurodegeneration. Notably, patients with Alzheimer’s disease (AD) exhibit decreased levels of brain-derived estrogen compared to age-matched healthy individuals, while peripheral estrogen levels remained similar. A loss of brain-derived estrogen may be a contributing factor of sexual dimorphism in neurodegenerative diseases. This question is particularly relevant to female health, as an epidemiological study across 195 countries reported 61.5% of AD patients are female, with earlier onset and more severe disease progression compared to males. I have established a model that better represents a sudden loss of brain-derived estrogen that has been seen in AD human brains. I injected 1mg/kg of letrozole in C57/BL6 wild-type mice daily for 30 days. Letrozole is a competitive inhibitor of aromatase and heralded as a "triumph of translational oncology" due to its high potency (~99% inhibition of aromatase) without affecting other steroidogenic pathways. Through this model, I have analyzed brains through molecular techniques including immunofluorescence and found a downregulation of collagen-IV, a key component of basal lamina in the BBB. I plan to further quantify markers of inflammation, blood-brain barrier integrity, and synaptic plasticity using immunofluorescence and western blotting to elucidate the mechanisms in which estrogen loss can increase vulnerability to neurodegeneration. This model lays the groundwork for better understanding the effect of decreased brain-derived estrogen on the development of neurodegeneration. Importantly, this model provides a translational approach to understanding how brain-derived estrogen can contribute to neurodegenerative risk, filling a gap at the intersection of neuroscience and endocrinology.

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