ESTROGEN ACTIVITY IN MICROGLIA AS A POTENTIAL PHARMACOLOGICAL TARGET FOR AD

The ultimate pharmacological goal in Alzheimer's disease (AD) intervention is to find treatments that will prevent AD before it occurs. Until recently, the therapeutic strategies in AD were focused on symptomatic remission and were devoted to replace or restore the cholinergic transmission; by the time intervention is initiated, neuronal function is compromised and therapy has very limited efficacy. Novel drugs are therefore under development with the aim to prevent or delay cell death. Among these, nonsteroidal anti-inflammatory drugs are efficacious in reducing AD incidence and progression; as a strong inflammatory reaction is associated with neuron loss in AD, inhibiting microglial secretion of inflammatory products is one of the most promising new lead in AD therapeutic targets. It is currently well accepted that mimicking the beneficial effects of estrogen on AD symptomatology is one of the important targets for developing novel therapeutic interventions. Estrogen is known to evoke different reactions in the CNS, by targeting neural cell survival, metabolism, synaptogenesis and signaling. On the basis of our recent findings of the anti-inflammatory activity of estrogen in brain inflammatory cells, we propose to address the novel question as to whether the down-regulation of the inflammatory response may be involved in the beneficial effects of estrogen on preserving brain integrity. This study will also allow to understand whether drugs of future use in menopausal women mimic or antagonize estrogen anti-inflammatory activity in the brain and therefore may be considered as candidates for preventive therapy of AD female patients.