High-energy compounds promote physiological processing of Alzheimer's amyloid-β precursor protein and boost cell survival in culture.

Physiological or α-processing of amyloid-β precursor protein (APP) prevents the formation of Aβ, which is deposited in the aging brain and may contribute to Alzheimer's disease. As such, drugs promoting this pathway could be useful for prevention of the disease. Along this line, we searched through a number of substances and unexpectedly found that a group of high-energy compounds (HECs), namely ATP, phosphocreatine, and acetyl coenzyme A, potently increased APP α-processing in cultured SH-SY5Y cells, whereas their cognate counterparts, i.e., ADP, creatine, or coenzyme A did not show the same effects. Other HECs such as GTP, CTP, phosphoenol pyruvate, and S-adenosylmethionine also promoted APP α-processing with varying potencies and the effects were abolished by energy inhibitors rotenone or NaN(3). The overall efficacy of the HECs in the process ranged from three- to four-fold, which was significantly greater than that exhibited by other physiological stimulators such as glutamate and nicotine. This suggested that the HECs were perhaps the most efficient physiological stimulators for APP α-processing. Moreover, the HECs largely offset the inefficient APP α-processing in aged human fibroblasts or in cells impaired by rotenone or H(2) O(2). Most importantly, some HECs markedly boosted the survival rate of SH-SY5Y cells in the death process induced by energy suppression or oxidative stress. These findings suggest a new, energy-dependent regulatory mechanism for the putative α-secretase and thus will help substantially in its identification. At the same time, the study raises the possibility that the HECs may be useful to energize and strengthen the aging brain cells to slow down the progression of Alzheimer's disease.