Role of immunity in the neuroprotective effect of estrogens: molecular mechanism and implications for Parkinson's disease

Epidemiological data have evidenced a significant gender difference in the incidence rate of Parkinson’s

disease (PD), with a greater susceptibility found in men compared with women, while the risk of

developing the disease is increased in women at menopause. Similarly, experimental studies conducted in

animal models of PD have shown that males are more susceptible than females to the effects of

neurotoxic stimuli, further supporting the existence of a gender-related vulnerability of the nigrostriatal

pathway, the brain area targeted in PD. These data suggest the incidence of gender-related differences in

the underlying pathophysiology of the disease and have implications for responsiveness to treatment. The

differential vulnerability between the two sexes has been ascribed, at least in part, to the activity of

estrogens, hormones that directly regulate the nigrostriatal neuronal pathway to provide neurotrophic and

protective support. Estrogens are synthesized in selected developmental periods and in a gender-specific

manner, and their synthesis drastically declines in female individuals at menopause. These hormones

modulate a large variety of physiological processes through the interaction with specific intracellular

receptor proteins: estrogen receptor-alpha (ERα) and –beta (ERβ). ERs have emerged as an attractive

biological system to control the evolution of selected disorders and recent academic and industrial efforts

in estrogenic drug discovery have provided new compounds endowed with higher potency and selectivity,

as well as reduced side effects.

In the past decade, neuroinflammation has emerged as an important substrate for PD. Epidemiological

studies have reported an inverse correlation between the chronic assumption of non-steroidal antiinflammatory

drugs and the risk of developing the disease defining neuroinflammation as an important

therapeutic target for PD treatment. It was recently demonstrated that estrogens might also intervene in

innate immunity, particularly at the level of macrophage cells that drive the inflammatory reaction.

Recent data indicate that 17β-estradiol, the most abundant estrogenic hormone in female blood, directly

interacts with ERα, and can reduce the inflammatory response in diverse tissues, including brain, by

inhibiting the reactivity of macrophages towards inflammatory stimuli.

Despite the evidence showing a critical pathogenic role of macrophage cells in PD and the presence in

these cells of the estrogen signaling pathway that is known to drive the physiology of gender diversity,

little is known on the extent to which estrogens regulate macrophage physiology and how this crosstalk

may modulate gender-specific neuroinflammation in PD. Based on published data and preliminary work

obtained by the proposing groups, the working hypothesis of this project postulates that estrogens

influence the phenotype of brain macrophages that reside or infiltrate the histopathological sites of PD,

and thus trigger a beneficial effect on the neurodegenerative process. Therefore, the main objective of

this proposal will be to understand the extent to which sexual dimorphism and estrogen signaling in

macrophage cell can influence neuroinflammatory processes associated with PD. Our research activity will

be organized in distinct work packages that will progressively explore the role of gender and estrogenic

hormones on macrophage activation and neuroinflammation both in vitro in primary macrophage culture,

and in vivo in animal models of PD. Ultimately, expression of gender-specific genes in response to

exogenous inflammatory stimuli will be evaluated in peripheral blood monocytes of male and female PD

patients.

In summary, our research will allow the identification of neuroinflammatory molecules and pathways that

may potentially translate into novel leads for research and development of innovative, gender-specific

therapeutic strategies, as well as into candidate biomarkers for predicting the susceptibility of developing

PD. Considering that inadvertent exposure to environment or pathological estrogenic signals during early

life induces a lifelong biological difference, the proposed evaluation of the programming activity of these

hormones on innate immunity will help understanding whether predisposition to PD may also have an

endocrine origin.