Choline acetyltransferase mRNA expression in the striatal neurons of patients with Alzheimer's disease

Abstract

Besides cortical pathology, Alzheimer's disease (AD) is associated with a massive loss of cholinergic neurons in the basal forebrain. The resulting cortical cholinergic depletion is thought to contribute to the major cognitive impairment described in AD. A selective loss of cholinergic neurons has also been observed in the ventral striatum, despite the lack of any major neurochemical dysfunction in the striatum of patients with AD. To examine possible changes in the functional activity of the neurons that remain in the striatum of AD patients, the expression level of the gene coding for choline acetyltransferase (ChAT) was evaluated using in situ hybridization in the caudate nucleus, putamen and ventral striatum. Quantitative analysis showed (i) a marked decrease in the number of ChAT mRNA-positive neurons in the ventral striatum, and (ii) significantly reduced ChAT mRNA expression in the surviving cholinergic neurons of the ventral striatum, whereas it was only slightly decreased in those of the dorsal striatum. Our data support the hypothesis of a down-regulated expression of ChAT in striatal cholinergic neurons, especially in those most vulnerable to the neurodegenerative process. The subnormal ChAT mRNA content may be the consequence of changes in the level of transcription of the ChAT gene, possibly in relation to sustained suffering still present at the late stages of this disease. Furthermore, the involvement of the ventral striatum in Alzheimer's disease may account for some of the behavioral and motor dysfunctions often observed in patients with AD.