Research Paper Volume 10, Issue 9 pp 2316—2337

The etiological effect of a new low-frequency ESR1 variant on Mild Cognitive Impairment and Alzheimer’s Disease: a population-based study

Figure 3. Functional study of rs9340803. (A) Relative luciferase activity assay performed with 293T cell line (repeated four times). Firefly luciferase expression was normalized using activity of renilla luciferase. Ratio of the normalized firefly luciferase expression to that of control was used to represent relative luciferase activity. Data represented the mean+s.d. (B) Postulated pathway diagram of estradiol-ER-cholesterol-Aβ formation cycle. Cholesterol-originated estrogen binds to ERα and regulates key enzymes in the cholesterol metabolism. Decreased ESR1 expression caused by rs9340803 A to G variation may disrupt the balance of adequate cholesterol content in the cytoplasm and on the cytomembrane of neuron as a result of decreased ERα activity on those key enzymes, promoting more Aβ production. Red line indicates the direct effect of estrogen ligand and Erα through BACE and black line refers to indirect effect by rugulation of cholesterol content. DHEA: dehydroepiandrosterone; StAR: steroidogenic acute regulatory protein; TSPO: translocator protein; ARO: aromatase.