Exploring the diverse signaling mechanisms of 17β-estradiol deficiency and replacement: Impacts on cognitive dysfunction in a post-menopausal experimental model

This study aimed to investigate brain signaling mechanisms affected by estradiol deficiency during menopause and how these pathways are modified with 17β-estradiol replacement to mitigate menopause-related changes, particularly in cognitive function and neuroinflammation, which are linked to the risk of dementia. Forty female white albino rats were divided into four groups: control, sham, ovariectomized (OVX), and OVX rats treated with 17β-estradiol. Cognitive tests using the Morris Water Maze assessed spatial learning and memory, while neurotransmitter levels were analyzed via HPLC. Serum levels of estrogen, Nerve Growth Factor (NGF), amyloid precursor protein(Aβ), and Postsynaptic Density Protein 95 (PSD-95) were measured using ELISA. Additionally, RT-PCR was used to evaluate the expression of gap junction protein connexin-43 (Cx43), Lipoprotein receptor-related protein (LRP1), and receptor for advanced glycation end products (RAGE), and aromatase expression was assessed via immunohistochemistry. Results showed that estrogen deficiency in OVX rats led to significant impairments in cognition, neurotransmitter signaling, and neurotrophic factors. Reduced NGF and altered PSD-95 levels indicated compromised neuronal health and synaptic plasticity. Increased aromatase expression reflected reduced local estrogen synthesis, potentially contributing to cognitive deficits. Upregulated RAGE and altered LRP1 expression suggested inflammatory and neurodegenerative processes, while decreased Cx43 expression and modified Aβ processing indicated impaired intercellular communication. Overall, the findings highlight the detrimental effects of estrogen deficiency on brain function and suggest that 17β-estradiol replacement may mitigate menopause-related cognitive decline and neuroinflammation.