Nontoxic Amyloid β Peptide1-42 Suppresses Acetylcholine Synthesis

Abstract

We show here that amyloid b peptide1– 42 (Ab1– 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. Ab1– 42 freshly solubilized in water (non-aged Ab1– 42), which was not neurotoxic without preaggregation, suppressed acetylcholine (ACh) synthesis in cholinergic neurons at very low concentrations (10 –100 nM), although non-aged Ab1– 40 was ineffective. Non-aged Ab1– 42 impaired pyruvate dehydrogenase (PDH) activity by activating mitochondrial t protein kinase I/glycogen synthase kinase-3b, 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 Ab1– 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 Ab1– 42 may disturb cholinergic function, leading to the deterioration of memory and cognitive function that is characteristic of AD.