Cholinergic deficits in
Alzheimer's disease are typically assessed by
choline acetyltransferase, the
enzyme that synthesizes
acetylcholine. However, the determining step in
acetylcholine formation is
choline uptake via a high affinity transporter in nerve terminal membranes. Evaluating uptake is difficult because regulatory changes in transporter function decay rapidly postmortem. To overcome this problem, brain regions from patients with or without
Alzheimer's disease were frozen within 4 h of death and examined for both
choline acetyltransferase activity and for binding of [3H]-
hemicholinium-3 to the
choline transporter. Consistent with the loss of
cholinergic projections, cerebral cortical areas exhibited marked decreases in
enzyme activity whereas the putamen, a region not involved in
Alzheimer's disease, was unaffected. However, [3H]
hemicholinium-3 binding was significantly enhanced in the cortical regions. In the frontal cortex, the increase in [3H]
hemicholinium-3 binding far exceeded the loss of
choline acetyltransferase, indicating transporter overexpression beyond that necessary to offset loss of synaptic terminals. These results suggest that, in
Alzheimer's disease, the loss of
cholinergic function is not dictated simply by destruction of nerve terminals, but rather involves additional alterations in
choline utilization; interventions aimed at increasing the activity of cholinergic neurons may thus accelerate neurodegeneration.