| Abstract: | Estrogen reduces the risk of Alzheimer disease (AD) in postmenopausal women, β‐amyloid (Aβ) burden in animal models of AD, and secretion of Aβ from neuronal cultures. The biological basis for these effects remains unknown. Aβ is proteolytically derived from the β‐amyloid precursor protein (βAPP) within the secretory pathway by distinct enzymatic activities known as β‐ and gamma‐secretase. Aggregated Aβ peptides are found predominantly within extraneuronal space and are believed to initiate toxic and inflammatory cascades leading to neuronal death. The major population of secreted Aβ peptides is generated within the trans‐Golgi‐network (TGN), also the major site of βAPP residence in neurons at steady state. Utilizing cell‐free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17β‐estradiol (17β‐E2) stimulates formation of vesicles containing βAPP, from the TGN. Accelerated βAPP trafficking precludes maximal Aβ generation within the TGN. 17β‐E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti‐Aβ effects by regulating βAPP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17β‐E2 may act in estrogen‐responsive tissues and illustrate how altering the kinetics of a protein's transport can influence its metabolic fate. |
