The choline-leakage hypothesis for the loss of acetylcholine in Alzheimer's disease

• Published in: Biophysical journal 1997-09, Vol.73 (3), p.1276-1280
• Main Authors: Ehrenstein, G., Galdzicki, Z., Lange, G.D.
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Age of Onset; Aging; Alzheimer Disease - metabolism; Amyloid beta-Peptides - biosynthesis; Brain - metabolism; Cell Membrane - metabolism; Choline - metabolism; Humans; Kinetics; Mathematics; Models, Neurological
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(97)78160-8

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.