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High‐energy compounds promote physiological processing of Alzheimer's amyloid‐β precursor protein and boost cell survival in culture
Author(s) -
Sawmiller Darrell R.,
Nguyen Huey T.,
Markov Olga,
Chen Ming
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07923.x
Subject(s) - rotenone , amyloid precursor protein , biochemistry , phosphocreatine , cell culture , creatine , oxidative stress , glutamate receptor , biology , chemistry , microbiology and biotechnology , pharmacology , endocrinology , medicine , alzheimer's disease , mitochondrion , disease , energy metabolism , genetics , receptor
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 ( HEC s), namely ATP , phosphocreatine, and acetyl coenzyme A, potently increased APP α‐processing in cultured SH ‐ SY 5Y cells, whereas their cognate counterparts, i.e., ADP , creatine, or coenzyme A did not show the same effects. Other HEC s 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 HEC s 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 HEC s were perhaps the most efficient physiological stimulators for APP α‐processing. Moreover, the HEC s 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 HEC s markedly boosted the survival rate of SH ‐ SY 5Y 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 HEC s may be useful to energize and strengthen the aging brain cells to slow down the progression of Alzheimer's disease.