Estrogen Enhances Uptake of Amyloid β‐Protein by Microglia Derived from the Human Cortex

Abstract

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 clearance of amyloid β-peptide (Aβ). In the periphery, estrogen both increases macrophage phagocytosis and has antiinflammatory effects. If estrogen had 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 Aβ deposits in the AD brain, little is known about the effects of estrogen on CNS microglia. Therefore, we sought to determine the relationship between estrogen treatment and internalization of Aβ by microglia by quantifying the internalization of aggregated Aβ by human cortical microglia. Aβ uptake was found to be dose- and time-dependent in cultured microglia. Increased Aβ uptake was observed at 1.5 and 24 h after addition of aggregated Aβ (50, 100, or 1,000 nM Aβ), and this uptake was enhanced by pretreatment with estrogen. The expression of estrogen receptor (ER) β (ER-β) was also up-regulated by estrogen treatment. Cells cotreated with ICI 182,780, an ER antagonist, showed significantly reduced internalization of Aβ in cultured microglia. These results indicate that microglia express an ER-β but that the effect of estrogen on enhancing clearance of Aβ may be related to the receptor-independent action of estrogen or to nonclassical ER effects of estrogen. Thus, stimulation of the ER might contribute to the therapeutic action of estrogen in the treatment of AD.