ABSTRACT
Astrocytes participate in the development and resolution of neuroinflammation in numerous ways, including the release of cytokines and growth factors. Among many, astrocytes release transforming growth factors beta (TGF-ß) TGF-ß1, TGF-ß2 and TGF-ß3. TGF-ß1 is the most studied isoform, while production and release of TGF-ß2 and TGF-ß3 by astrocytes have been poorly characterized. Here, we report that purified cultures of hippocampal astrocytes produce mainly TGF-ß3 followed by TGF-ß2 and TGF-ß1. Furthermore, astrocytes release principally the active form of TGF-ß3 over the other two. Changes in release of TGF-ß were sensitive to the calcineurin (CaN) inhibitor FK506. Starvation had no effect on TGF-ß1 and TGF-ß3 while TGF-ß2 mRNA was significantly up-regulated in a CaN-dependent manner. We further investigated production and release of astroglial TGF-ß in Alzheimer's disease-related conditions. Oligomeric ß-amyloid (Aß) down-regulated TGF-ß1, while up-regulating TGF-ß2 and TGF-ß3, in a CaN-dependent manner. In cultured hippocampal astrocytes from 3xTg-AD mice, TGF-ß2 and TGF-ß3, but not TGF-ß1, were up-regulated, and this was CaN-independent. In hippocampal tissues from symptomatic 3xTg-AD mice, TGF-ß2 was up-regulated with respect to control mice. Finally, treatment with recombinant TGF-ßs showed that TGF-ß2 and TGF-ß3 significantly reduced PSD95 protein in cultured hippocampal neurons, and this effect was paralleled by conditioned media from Aß-treated astrocytes or from astrocytes from 3xTg-AD mice. Taken together, our data suggest that TGF-ß2 and TGF-ß3 are produced by astrocytes in a CaN-dependent manner and should be investigated further in the context of astrocyte-mediated neurodegeneration.
