Reduced expression of NO-sensitive guanylyl cyclase in reactive astrocytes of Alzheimer disease, Creutzfeldt–Jakob disease, and multiple sclerosis brains

Abstract

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.

Keywords

• Astroglia
• Cyclic GMP
• Soluble guanylyl cyclase
• Nitric oxide
• Alzheimer's disease
• Creutzfeldt–Jakob disease