Investigating the Potential Impact of LH on the Progression of Alzheimer’s Disease via Microglia Activation and C/EBPβ pathway

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disease that causes irreversible cognitive decline and memory loss. The disproportionate effect of AD on postmenopausal women prompts investigation into the role of hormonal changes in disease pathogenesis. However, previous studies on estrogen replacement therapies have shown inconsistent results. Therefore, further confirmation is needed to ensure the independent effects of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) on AD pathology. Our study will 1) focus on microglial activation pathway 2) focus on the LH-C/EBPβ-AEP pathway and its potential influence on AD progression.Methods: Using cell lines to investigate whether microglial activation is present. HMC3 cells will be treated with LH or control phosphate buffered saline (PBS). Carry out Western Blot (WB) and qPCR to confirm presence of cytokines, which is the product of microglial activation. Using 3xTg-AD mice treated with LH or control PBS. To identify AD progression, immunofluorescent (IF) micrograph will be used to quantify amyloid-beta (Aβ) load. WB and qPCR will be used to identify cytokines. Morris water maze (MWM) will be carried out for cognitive testing. Using an ovariectomized mice model to investigate the LH-C/EBPβ-AEP pathway. Mice will be treated with LH antibodies or control IgG, followed by assessments using IVIS imaging and MWM test to measure spatial memory. IF, WB and qPCR will be used to quantify Aβ and Tau protein levels and gene expression changes. Furthermore, the study will explore the precise relationship between LH and C/EBPβ expression through inhibition experiments targeting AKT and ERK1/2 signaling pathways.Expected results: Our hypothesis is that LH activates microglia, with both pro-inflammatory and anti-inflammatory cytokine released. This change in microglia function suggests LH has an effect on microglia and hence removal of Aβ plaques. Another hypothesis is that LH antibody manages to cross the blood-brain barrier. The cognitive ability will be improved in LH-Ab treated mice with reduced Aβ and Tau protein levels and downregulation of the C/EBPβ–AEP/δ-secretase pathway. Simultaneously, we expect that there will be a positive correlation between LH levels and expression of C/EBPβ-related pathways, suggesting the involvement of AKT and ERK1/2 signaling pathways in AD progression.Conclusion: This study aims to provide evidence for the link between LH activation of the C/EBPβ pathway and AEP production, promoting our understanding of AD pathogenesis. The insights gained may implicate therapeutic strategies targeting LH mechanisms in postmenopausal women at risk of AD.