ENHANCED HEMICHOLINIUM BINDING AND ATTENUATED DENDRITE BRANCHING IN COGNITIVELY IMPAIRED ACETYLCHOLINESTERASE-TRANSGENIC MICE

In a search for behavioral, neuroanatomical, and metabolic characteris tics of Alzheimer's disease that may result from cholinergic malfuncti on,we used transgenic mice overexpressing acetylcholinesterase (AChE) mRNA and active enzyme in brain neurons. Mapping by in situ hybridizat ion revealed that transgenic and host AChE mRNAs were distributed simi larly. In a Morris water maze working memory paradigm, adult transgeni c mice did not display the characteristic improvement found in control mice either between or within test days and spent less time than cont rol mice in the platform zone. In 5-week-old transgenic mice, the basi lar dendritic trees of layer 5 pyramidal neurons from the frontopariet al cortex were essentially as developed as in age-matched controls. Ho wever, branching totally ceased after this age, whereas in control adu lts it continued up to at least 7 months. Therefore, dendritic arbors became smaller in adult transgenic mice than those of controls. Furthe rmore, the average number of spines was significantly lower on dendrit ic branches of 7-month-old but not 5-week-old transgenics as compared with controls. Binding of tritiated hemicholinium-3, a blocker of the high-affinity choline uptake characteristic of active cholinergic term inals, was over twofold enhanced in the brain of transgenic mice. In c ontrast, no differences were observed in the mRNA and ligand binding l evels of several different subtypes of nicotinic and muscarinic acetyl choline receptors. These findings suggest that three different hallmar ks associated with Alzheimer's disease-namely, progressive cognitive f ailure, cessation of dendrite branching and spine formation, and enhan ced high-affinity choline uptake-are outcomes of cholinergic malfuncti on.