Gonadal hormone modulation of chronic neuroinflammation

Abstract

Post-menopausal women have an increased incidence of Alzheimer's disease (AD) that may be delayed in onset by estrogen replacement therapy (ERT). Estrogen has many neuroprotective and neurotrophic proclivities; therefore, its decline with menopause may leave the brain vulnerable to toxic insults stemming from disease states. Recent clinical trials investigating ERT as a treatment for AD found beneficial effects following short-term treatment that become attenuated, and possibly reversed, following longer treatment intervals. This doctoral dissertation examined the interaction of two conditions known to exist within the female AD brain: the presence of chronic neuroinflammation and either estrogen deprivation or chronic ERT. As the duration of treatment and regimen of estrogen administration may alter the effectiveness of ERT, chronic and fluctuating administration of estrogen were assessed against the behavioral, biochemical and pathological consequences of short- and long-term neuroinflammation in the female rat brain. Overall, the results suggest a strong interaction between neuroendocrine and autonomic function in the female brain with neuroinflammation. In the presence of chronic neuroinflammation, the brain differentially responds depending on the hormone status of the animal. Cognitive performance is impaired with neuroinflammation or constant estrogen; the combined occurrence of both conditions worsened performance more than either condition presented alone. However, gonadally intact females with neuroinflammation were unimpaired on the task and had approximately half the number of activated microglia. The pattern of activated microglia is unique to the female brain and highlights an interesting distribution not seen in male rats. Specifically, an elegant map of activated microglia emerges of brain areas involved in autonomic control, stress regulation and energy homeostasis. Regions showing the densest distribution of activated microglia are important autonomic relay stations that interconnect various brain regions conveying internal state information. Moreover, these regions have extensive bi-directional communication with both endocrine and immune systems, suggesting an extensive interaction occurring in the female brain capable of influencing multiple systems, including hormone secretion, sympathetic output, immune function and behavioral processes. This dissertation proposes that the interactions between these systems have important consequences for post-menopausal women with AD and are likely to underlie the varying effects seen with ERT.