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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 NaN3. 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 H2O2. 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.
A prominent feature of brain aging and Alzheimer's disease (AD) is the deposition of Aβ, a proteolytic fragment of amyloid-β precursor protein (APP). Physiological or α-processing of APP prevents the formation of Aβ (Esch et al. 1990; Walsh and Selkoe 2004), but this pathway is somehow inactivated during aging with a concomitant increase of Aβ, reflecting a proteostasis failure (Lannfelt et al. 1995; Kern et al. 2006). It has been found that activation of APP α-processing inevitably decreases Aβ, and vice versa (Skovronsky et al. 2000; Frautschy et al. 1998; Etcheberrigaray et al. 2004). As such, drugs promoting APP α-processing would potentially benefit the aging brain. Along this line, a range of compounds have been found to exhibit such effects including growth factors, hormones, cytokines, and stimulators of neurotransmitter receptors and signaling transduction pathways. These compounds have been under intense studies to evaluate their therapeutic values (Lichtenthaler 2011; Sun and Alkon 2010; reviews).
In our laboratory, we have also tested a number of substances for their potencies to promote APP α-processing. These substances include, among others, current and experimental medications, herbal extracts, and nutritional supplements. The search has led us to unexpectedly find that a group of high-energy compounds (HECs) is highly effective in promoting APP α-processing. Subsequent experiments showed that they also boosted the survival of cultured neuronal cells impaired by energy inhibitors or oxidative stress.
High-energy compounds contain an energy-rich bond of either ~phosphoryl or ~acyl group, which upon hydrolysis liberates at least 7 kilocalories per mole of free energy (ΔGo) under standard conditions. There are many HECs in the body, the best known of which are adenosine, guanosine, or cytidine triphosphate (ATP, GTP, and CTP), phosphocreatine (PCr), acetyl-coA, phosphoenol pyruvate (PEP), and S-adenosylmethionine (SAM) (Lehninger 1975; Nicholls and Ferguson 2002). In CNS, free energy is the essential driving force for synthesis of macromolecules, fast axonal and dendritic transport, and maintenance of ion gradients (McDaniel et al. 2003; Bonda et al. 2009).