Nontoxic amyloid beta peptide 1-42 suppresses acetylcholine synthesis. Possible role in cholinergic dysfunction in Alzheimer's disease.
We show here that amyloid beta peptide1-42 (Abeta1-42) 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. Abeta1-42 freshly solubilized in water (non-aged Abeta1-42), which was not neurotoxic without preaggregation, suppressed acetylcholine (ACh) synthesis in cholinergic neurons at very low concentrations (10-100 nM), although non-aged Abeta1-40 was ineffective. Non-aged Abeta1-42 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 Abeta1-42 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 Abeta1-42 may disturb cholinergic function, leading to the deterioration of memory and cognitive function that is characteristic of AD.
Hoshi
M
M
Mitsubishi Kasei Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194, Japan.
Takashima
A
A
Murayama
M
M
Yasutake
K
K
Yoshida
N
N
Ishiguro
K
K
Hoshino
T
T
Imahori
K
K
D000109:Acetylcholine / Q000096:biosynthesis*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D008928:Mitochondria / Q000201:enzymology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011768:Pyruvate Dehydrogenase Complex; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000255:Adenosine Triphosphate; D000109:Acetylcholine