β-Amyloid Peptides Decrease Soluble Guanylyl Cyclase Expression in Astroglial Cells

In astroglial cells β-amyloid peptides (βA) induce a reactive phenotype and increase expression of NO synthase. Here we show that treatment of rat brain astrocytes with βA decreases their capacity to accumulate cyclic GMP (cGMP) in response to NO as a result of a decreased expression of soluble guanylyl cyclase (sGC) at the protein and mRNA levels. Potentiation of βA-induced NO formation by interferon-γ did not result in a larger decrease in cGMP formation and inhibition of NO synthase failed to reverse down-regulation of sGC, indicating that NO is not involved. The βA effect was prevented by the protein synthesis inhibitor cycloheximide. Intracerebral βA injection also decreased sGC β1 subunit mRNA levels in adult rat hippocampus and cerebellum. A loss of sGC in reactive astrocytes surrounding β-amyloid plaques could be a mechanism to prevent excess signalling via cGMP at sites of high NO production.