Estrogen enhances uptake of amyloid beta-protein by microglia derived fromthe human cortex

In recent years, inflammatory mechanisms have been increasingly appreciated as important steps in the pathology of Alzheimer's disease (AD), There are two pathological defects in AD: chronic inflammation and impaired clearanc e of amyloid beta-peptide (A beta), In the periphery, estrogen both increas es macrophage phagocytosis and has antiinflammatory effects. If estrogen ha d a similar effect in the CNS, it could reverse inflammatory defects in AD. Although microglia are a key component of the immune system and help clear A beta deposits in the AD brain, little is known about the effects of estr ogen on CNS microglia. Therefore, we sought to determine the relationship b etween estrogen treatment and internalization of A beta by microglia by qua ntifying the internalization of aggregated A beta by human cortical microgl ia. A beta uptake was found to be dose- and time-dependent in cultured micr oglia. Increased A beta uptake was observed at 1.5 and 24 h after addition of aggregated A beta (50, 100, or 1,000 nM A beta), and this uptake was enh anced by pretreatment with estrogen. The expression of estrogen receptor (E R) beta (ER-beta) was also up-regulated by estrogen treatment. Cells cotrea ted with ICI 182,780, an ER antagonist, showed significantly reduced intern alization of A beta in cultured microglia, These results indicate that micr oglia express an ER-beta but that the effect of estrogen on enhancing clear ance of A beta may be related to the receptor-independent action of estroge n or to nonclassical ER effects of estrogen, Thus, stimulation of the ER mi ght contribute to the therapeutic action of estrogen in the treatment of AD .