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Volume 272, Number 4, Issue of January 24, 1997 pp. 2038-2041
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

COMMUNICATION:
Nontoxic Amyloid beta  Peptide1-42 Suppresses Acetylcholine Synthesis
POSSIBLE ROLE IN CHOLINERGIC DYSFUNCTION IN ALZHEIMER'S DISEASE

(Received for publication, July 15, 1996, and in revised form, September 23, 1996)

Minako Hoshi , Akihiko Takashima , Miyuki Murayama , Kaori Yasutake , Natsuko Yoshida , Koichi Ishiguro , Toshimitsu Hoshino and Kazutomo Imahori

From the Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194, Japan

We show here that amyloid beta  peptide1-42 (Abeta 1-42) may play a key role in the pathogenesis of the cholinergic dysfunction seen in Alzheimer's disease (AD), in addition to its putative role in amyloid plaque formation. Abeta 1-42 freshly solubilized in water (non-aged Abeta 1-42), which was not neurotoxic without preaggregation, suppressed acetylcholine (ACh) synthesis in cholinergic neurons at very low concentrations (10-100 nM), although non-aged Abeta 1-40 was ineffective. Non-aged Abeta 1-42 impaired pyruvate dehydrogenase (PDH) activity by activating mitochondrial tau  protein kinase I/glycogen synthase kinase-3beta , as we have already shown in hippocampal neurons (Hoshi, M., Takashima, A., Noguchi, K., Murayama, M., Sato, M., Kondo, S., Saitoh, Y., Ishiguro, K., Hoshino, T., and Imahori, K. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 2719-2723). Neither choline acetyltransferase activity nor choline metabolism was affected. Therefore, the major cause of reduced ACh synthesis was considered to be an inadequate supply of acetyl-CoA owing to PDH impairment. Soluble Abeta 1-42 increases specifically in AD brain (Kuo, Y.-M., Emmerling, M. R., Vigo-Pelfrey, C., Kasunic, T. C., Kirkpatrick, J. B., Murdoch, G. H., Ball, M. J., and Roher, A. E. (1996) J. Biol. Chem. 271, 4077-4081). This increase in soluble Abeta 1-42 may disturb cholinergic function, leading to the deterioration of memory and cognitive function that is characteristic of AD.


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