Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 47, Issue 3, Pages 211-221Publisher
WILEY
DOI: 10.1111/ejn.13819
Keywords
Alzheimer's disease; calcineurin; neurodegeneration; PSD95
Categories
Funding
- Fondazione Cariplo [2013-0795, 2014-1094]
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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-) TGF-1, TGF-2 and TGF-3. TGF-1 is the most studied isoform, while production and release of TGF-2 and TGF-3 by astrocytes have been poorly characterized. Here, we report that purified cultures of hippocampal astrocytes produce mainly TGF-3 followed by TGF-2 and TGF-1. Furthermore, astrocytes release principally the active form of TGF-3 over the other two. Changes in release of TGF- were sensitive to the calcineurin (CaN) inhibitor FK506. Starvation had no effect on TGF-1 and TGF-3 while TGF-2 mRNA was significantly up-regulated in a CaN-dependent manner. We further investigated production and release of astroglial TGF- in Alzheimer's disease-related conditions. Oligomeric -amyloid (A) down-regulated TGF-1, while up-regulating TGF-2 and TGF-3, in a CaN-dependent manner. In cultured hippocampal astrocytes from 3xTg-AD mice, TGF-2 and TGF-3, but not TGF-1, were up-regulated, and this was CaN-independent. In hippocampal tissues from symptomatic 3xTg-AD mice, TGF-2 was up-regulated with respect to control mice. Finally, treatment with recombinant TGF-s showed that TGF-2 and TGF-3 significantly reduced PSD95 protein in cultured hippocampal neurons, and this effect was paralleled by conditioned media from A-treated astrocytes or from astrocytes from 3xTg-AD mice. Taken together, our data suggest that TGF-2 and TGF-3 are produced by astrocytes in a CaN-dependent manner and should be investigated further in the context of astrocyte-mediated neurodegeneration.
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