The Relationship between Choline Acetyltransferase and Nitric Oxide Synthase Isoform Expression in Alzheimer’s Disease

Abstract

Nitric oxide (NO) plays an important role in cholinergic neurotransmission and has been implicated in the progression of Alzheimer’s disease (AD). Cholinergic neurotransmission has been associated with regulation of NO synthase (NOS) expression, and we determined previously that NO modulates choline acetyltransferase (ChAT) expression. In spite of the important links identified between NOS and ChAT, little is known about the relationship between these two enzymes in AD. Therefore in the present study, we compared the expression levels of ChAT and NOS in necropsy brain of individuals with AD and non-demented controls. ChAT and NOS levels were assessed in control and AD caudate, nucleus basalis of Meynert (nbM), cortex and hippocampus by radioenzymatic assay, immunoblot analysis and RT-PCR. We detected a significant decrease in ChAT activity in the cortex of AD cases, but no alterations in NOS activity were observed in any of the brain regions examined. At the mRNA level, no significant decrease in total ChAT mRNA was detected but the decrease in M-ChAT mRNA levels approached significance in the nbM. No difference in nNOS and iNOS mRNA and protein levels was observed between control and AD tissue in any of the four brain regions sampled, but a statistically significant decrease in eNOS mRNA levels was detected in both the cortex and hippocampus of AD brain. Finally, the levels of ChAT and NOS activity, protein or mRNA isoforms did not correlate in most of the brain regions examined, but a reduction in ChAT activity and eNOS mRNA in basal forebrain projection regions was observed. These data suggest that in general, there is no correlation between the levels of NOS and ChAT in control or AD subjects, but a reduction in eNOS levels in the hippocampus and cortex indicates there could be an interaction between eNOS containing cells and basal forebrain projections neurons in AD.