The choline-leakage hypothesis for the loss of acetylcholine in Alzheimer's disease.
We present a hypothesis for the loss of acetylcholine in Alzheimer's disease that is based on two recent experimental results: that beta-amyloid causes leakage of choline across cell membranes and that decreased production of acetylcholine increases the production of beta-amyloid. According to the hypothesis, an increase in beta-amyloid concentration caused by proteolysis of the amyloid precursor protein results in an increase in the leakage of choline out of cells. This leads to a reduction in intracellular choline concentration and hence a reduction in acetylcholine production. The reduction in acetylcholine production, in turn, causes an increase in the concentration of beta-amyloid. The resultant positive feedback between decreased acetylcholine and increased beta-amyloid accelerates the loss of acetylcholine. We compare the predictions of the choline-leakage hypothesis with a number of experimental observations. We also approximate it with a pair of ordinary differential equations. The solutions of these equations indicate that the loss of acetylcholine is very sensitive to the initial rate of beta-amyloid production.
Ehrenstein
G
G
Biophysics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. gerry@helix.nih.gov
Galdzicki
Z
Z
Lange
G D
GD
D000109:Acetylcholine / Q000378:metabolism*; D017668:Age of Onset; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D001921:Brain / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002794:Choline / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D008959:Models, Neurological
D016229:Amyloid beta-Peptides; D002794:Choline; D000109:Acetylcholine