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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.

In Alzheimer's disease (AD) brains increased NO synthase (NOS) expression is found in reactive astrocytes surrounding amyloid plaques. We have recently shown that treatment with β-amyloid peptides or IL-1β down-regulates NO-sensitive soluble guanylyl cyclase (sGC) in cultured astrocytes and in adult rat brain. In this work, we have examined sGC activity and expression in postmortem brain tissue of AD patients and matched controls. No significant alteration was observed in basal or NO-stimulated sGC activity, nor in sGC β1 and α1 subunit levels in cortical extracts of AD brains. Immunohistochemistry showed intense and widespread labeling of sGC β1 in cortical and hippocampal neurons and white matter fibrillar astrocytes, while grey matter astrocytes were faintly stained. In AD, expression of sGC in neurons and fibrillar astrocytes is not altered but is markedly reduced in reactive astrocytes surrounding amyloid plaques. Immunostaining for sGC β1 was also lacking in reactive astrocytes in cortex and subcortical white matter in Creutzfeldt–Jakob disease brains and in subacute and chronic plaques in multiple sclerosis (MS) brains. Thus, induction of astrocyte reactivity is associated with decreased capacity to generate cGMP in response to NO both in vitro and in vivo. This effect may be related to the development of the astroglial inflammatory response.