Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPARγ expression in cultured astrocytes

Inflammation has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). The main inflammatory players in AD are the glial cells which initiate the inflammatory response. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Aβ deposition. It is desirable to find methods of tipping the balance towards anti-inflammatory state. Estrogenic compounds have shown anti-inflammatory and also antioxidant activity. Astrocytes were pretreated with 17-βestradiol or with genistein, and 48 h later treated with 5 μM amyloid beta (Aβ) for 24 h. We found that Aβ induces inflammatory mediators, such as cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α). All these effects were prevented when cells were pretreated with estradiol or genistein, demonstrating anti-inflammatory effects of estradiol or genistein in astrocytes in primary culture. The Aβ-stimulated expression of pro-inflammatory genes in cells is antagonized by the action of the PPARs (peroxisome proliferator activated receptors). Here we detected an increase in PPAR-γ expression in astrocytes in primary culture treated with Aβ and estradiol or soy isoflavone genistein. Thus, some of the anti-inflammatory effects of estrogenic compounds may be mediated and activated by PPARs suppressing a diverse array of inflammatory responses caused by Aβ in astrocytes in primary culture.