Vesicular acetylcholine transporter density and Alzheimer's disease

We have evaluated the vesamicol analogue meta-[¹²⁵I]iodobenzyltrozamicol {(+)-[¹²⁵I]MIBT} as a probe to assess cholinergic terminal integrity in the human temporal cortex. Saturation binding analysis, using 5-aminobenzovesamicol (ABV) to define nonspecific binding, revealed a high-affinity binding site with a K(d) value of 4.3 ± 1.2 nM in the temporal cortex of the young control subjects. Similar affinity values were observed for (+-)-[¹²⁵I]MIBT binding in aged control subjects (K(d) = 3.4 ± 0.5 nM) and AD patients (K(d) = 3.0 ± 0.8 nM). In contrast, Bmax values for young subjects, aged controls and AD patients were 31.2 ± 6.3, 17.0 ± 2.0 and 9.4 ± 1.6 pmol/g, respectively, clearly reflecting significant reductions in (+)-[¹²⁵I]MIBT binding site density with aging and age-related neuropathology. Moreover, the decrease in (+)-[¹²⁵I]MIBT binding was correlated with choline acetyltransferase activities (r = 0.72) in the AD temporal cortex. These results suggest that when selective ligands are used, the vesicular acetylcholine transporter can be a useful marker protein for assessing the loss of cholinergic projections in AD and related disorders.