Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.
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.
Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
T A
TA
Slotkin
C B
CB
Nemeroff
G
G
Bissette
F J
FJ
Seidler
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D001344:Autopsy; D002352:Carrier Proteins / Q000096:biosynthesis*; D002540:Cerebral Cortex / Q000378:metabolism*; D002794:Choline / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D006426:Hemicholinium 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D008875:Middle Aged; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C065637:choline transporter; D006426:Hemicholinium 3; D002795:Choline O-Acetyltransferase; D002794:Choline