High affinity choline transporter status in Alzheimer's disease tissue from rapid autopsy.
The degeneration of nucleus basalis cholinergic neurons in Alzheimers disease (AD) has led to therapies that attempt to increase the synaptic availability of acetylcholine in the remaining cholinergic nerve terminals and to thereby reverse or slow the progressive dementia accompanying the disease process. The inadequacy of current choline-replacement therapies suggests that utilization of choline may be disordered and the rate-limiting step in acetylcholine synthesis, the high affinity choline transporter, may be involved. An adequate test of this hypothesis requires the use of fresh, unfrozen tissue, as the transporter activity declines rapidly after death. Using tissue acquired within two hours of death, the activity of the high affinity choline transporter was shown to be increased in cortical brain regions from AD patients compared to non-AD controls. Further studies using frozen tissues with similar short postmortem acquisition times, revealed the expression of the high affinity uptake transporter to be increased in AD cortex as well. When the ratio of regional uptake activity or expression to the regional level of choline acetyltransferase was calculated, the increase in choline transporter activity and expression was clearly statistically significant. Further statistical significance in the choline transporter activity of the AD group was achieved when the putamen, a region without marked pathology in AD, was used as an internal standard to control for agonal state differences in the individual patients contributing tissue to this study. These increases in choline transporter expression and activity in AD indicate disordered regulation of this rate-limiting component of acetylcholine synthesis above and beyond that required to compensate for the reduced cholinergic synaptic availability in AD.
Bissette, G; Seidler, FJ; Nemeroff, CB; Slotkin, TA
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