Aromatase enzyme and Alzheimer's disease

Abstract

Aromatase enzyme encoded by CYP19 gene is responsible for the formation of estrone and estradiol from C19 androgens, androstenedione and testosterone. Several lines of evidence suggest an important role for the estrogens as well as androgens in the key pathogenic processes of Alzheimer's disease (AD) such as amyloid beta (Abeta) production, hyperphosporylation of tau protein, oxidative stress and apoptosis. Moreover, epidemiological studies suggest a neuroprotective role for estrogen in AD for which reason estrogen replacement therapies have been extensively studied as a way to improve the cognition and to lower the risk of AD. Aromatase enzyme is a key player in this context as it controls estrogen biosynthesis and, therefore, it may exert neuroprotective effects via increasing the local estrogen levels in injured neurons. Consistent with this idea, brain injury in mice and rats rapidly up-regulates aromatase enzyme expression in glial cells at the injury site suggesting that aromatase may be involved in protection of injured neurons through increased estrogen levels. Additional support for the role of aromatase in AD originates from the recent genetic studies, which have shown that single nucleotide polymorphisms in CYP19 gene are independently or in synergy with other AD risk genes increasing the susceptibility for AD. These genetic findings suggest that CYP19 gene encompasses functional alterations, which may affect stability, expression or activity of the aromatase enzyme. Characterization of these novel alternations may ultimately reveal new avenues to understand and design new therapeutic approaches to AD.